Emerging roles of F-box proteins in cancer drug resistance

Drug Resistance Updates 49 (2020) 100673

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Emerging roles of F-box proteins in cancer drug resistance a,1

Linzhi Yan , Min Lin Xueqiong Zhua,** a b c

a,1

a

b,

T a,c,

, Shuya Pan , Yehuda G. Assaraf ***, Zhi-wei Wang

*,

Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China The Fred Wyszkowski Cancer Research Lab, Faculty of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

A R T I C LE I N FO

A B S T R A C T

Keywords: Ubiquitination Drug resistance FBXW7 β-TrCP Skp2 Tumor

Chemotherapy continues to be a major treatment strategy for various human malignancies. However, the frequent emergence of chemoresistance compromises chemotherapy efficacy leading to poor prognosis. Thus, overcoming drug resistance is pivotal to achieve enhanced therapy efficacy in various cancers. Although increased evidence has revealed that reduced drug uptake, increased drug efflux, drug target protein alterations, drug sequestration in organelles, enhanced drug metabolism, impaired DNA repair systems, and anti-apoptotic mechanisms, are critically involved in drug resistance, the detailed resistance mechanisms have not been fully elucidated in distinct cancers. Recently, F-box protein (FBPs), key subunits in Skp1-Cullin1-F-box protein (SCF) E3 ligase complexes, have been found to play critical roles in carcinogenesis, tumor progression, and drug resistance through degradation of their downstream substrates. Therefore, in this review, we describe the functions of FBPs that are involved in drug resistance and discuss how FBPs contribute to the development of cancer drug resistance. Furthermore, we propose that targeting FBPs might be a promising strategy to overcome drug resistance and achieve better treatment outcome in cancer patients. Lastly, we state the limitations and challenges of using FBPs to overcome chemotherapeutic drug resistance in various cancers.

Introduction Cancer is one of the leading causes of death in the world, which leads to decreased life expectancy. Due to aging and population growth, increased cancer incidence and mortality worldwide have been documented (Bray et al., 2018). In 2018, there were 18.1 million new cancer cases worldwide and 9.6 million mortalities (Bray et al., 2018). Chemotherapeutic treatment is an effective therapy for patients with malignant tumors. However, primary and acquired resistance to chemotherapeutic drugs lead to dismal outcomes in human cancer patients (Assaraf et al., 2019; Levin et al., 2019; Shaked, 2019). Therefore, development of drug resistance is a central cause of treatment failure and consequently cancer-related deaths (Cui et al., 2018; Livney and Assaraf, 2013; Taylor et al., 2015; Wijdeven et al., 2016). The mechanisms of drug resistance in cancer treatment are still ambiguous. A large array of studies revealed that multiple mechanisms of cancer drug resistance exist including: decreased drug uptake,

enhanced drug efflux via ATP-binding cassette (ABC) transporters (Amawi et al., 2019; Li et al., 2016a), qualitative and quantitative alterations in drug target proteins, drug sequestration within intracellular or extracellular organelles, anti-apoptotic mechanisms, promotion of drug metabolism and detoxification systems, as well as dysregulation of DNA repair systems (Gonen and Assaraf, 2012; Niewerth et al., 2015; Taddia et al., 2015; Zhang et al., 2019b; Zhitomirsky and Assaraf, 2016) (Fig. 1). In recent years, F-box protein (FBP), as a subunit in Skp1Cullin1-F-box protein (SCF) E3 ligase complexes, has been validated to play pivotal roles in drug resistance development through ubiquitination and degradation of downstream substrates in various malignancies. Therefore, in the current article, the functions of FBPs in cancer drug resistance are delineated. We also describe how FBPs contribute to the development of drug resistance in various human malignancies. Furthermore, we propose that targeting FBPs might be a promising approach to surmount drug resistance and achieve better outcomes in cancer patients. Lastly, we highlight the limitations and challenges of

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Corresponding author at: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Corresponding author at: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, Zhejiang, 325027, China. ⁎⁎⁎ Corresponding author at: Faculty of Biology, Technion – Israel Institute of Technology, Haifa, 3200003, Israel. E-mail addresses: [email protected] (Y.G. Assaraf), [email protected] (Z.-w. Wang), [email protected] (X. Zhu). 1 Yan L and Lin M contributed equally to this work. ⁎⁎

https://doi.org/10.1016/j.drup.2019.100673 Received 8 November 2019; Received in revised form 2 December 2019; Accepted 4 December 2019 1368-7646/ © 2019 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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silenced FBXW7 (Yu et al., 2014). In addition, the miR-223/FBXW7 axis is associated with doxorubicin sensitivity in CRC via suppression of EMT (Ding et al., 2018a). Herein, abrogation of FBXW7 expression dramatically increased doxorubicin resistance in CRC. Similarly, an elegant study found that inhibition of FBXW7 expression by miR-223 led to an increased drug resistance to erlotinib in NSCLC cells (Zhang et al., 2017). Similarly, miR-223 overexpression which repressed target FBXW7 gene expression resulted in cisplatin resistance in gastric cancer cells (Zhou et al., 2015). Moreover, upregulated expression of miR-363 in gastric cancer patient specimens attenuated the efficacy of docetaxel, cisplatin, and 5-fluorouracil (5-FU) regimen via repression of FBWX7 expression (Zhang et al., 2016). There is an FBXW7 mutation in CRC, which directly disrupted the degradation of phosphorylated-p53 at Serine-15, leading to oxaliplatin resistance in CRC cells (Li et al., 2015). Consistently, another study found that FBXW7 deficiency is negatively correlated with CRC patient survival due to upregulation of Cryptochrome 2 (CRY2). Inversely, elevated FBXW7 and the resulting CRY2 deficiency dramatically accelerated the susceptibility of CRC cells to oxaliplatin (Fang et al., 2015). CRC stem cells exhibit chemoresistance due to increased FBXW7 levels and a subsequent degradation of c-Myc (Izumi et al., 2017). It has been found that blocking FBXW7 expression can decelerate the degradation of the pro-survival phosphorylated myeloid cell leukemia sequence 1 (MCL-1), causing chemoresistance to microtubuletargeted agents including paclitaxel and vincristine in cancer cells (Inuzuka et al., 2011; Wertz et al., 2011). Thus specifically, during mitotic arrest upon treatment with these cytotoxic agents, MCL-1 protein levels were reduced markedly, resulting in cell death induction. Phosphorylation of MCL-1 enhanced its binding by FBXW7, leading to degradation of MCL-1. MCL-1 destruction was abolished in patientderived tumor cells upon loss of FBXW7 or with loss-of-function mutations in FBXW7, contributing to resistance to anti-microtubule agents (Inuzuka et al., 2011; Wertz et al., 2011). Importantly, primary tumor specimens exhibited FBXW7 inactivation and MCL-1 upregulation, indicating the potential roles of these proteins in tumorigenesis (Inuzuka et al., 2011; Wertz et al., 2011). In addition, FBXW7 mutation failed to mediate the degradation of phosphorylated MCL-1 in a glycogen synthase kinase 3 beta (GSK3β)depended manner, which distinctly diminish the therapeutic efficiency of Heat shock protein 90 (Hsp90) in CRC (Tong et al., 2017a). Consistent with this observation, other studies uncovered that MCL-1 is positively correlated with resistance to cytotoxic agents including regorafenib and sorafenib which are multikinase inhibitors of RAS/RAF/ Mitogen-activated protein/Extracellular signal-regulated kinase (ERK) Kinase (MEK)/ERK signalling in CRC cells (Tong et al., 2017b). Increased FBXW7 levels enhanced the degradation of MCL-1, leading to a reversal of chemoresistance in CRC cells (Tong et al., 2017b, c). Expectedly, a selective MCL-1 inhibitor restored regorafenib sensitivity of CRC cells with intrinsic or acquired resistance. Furthermore, depletion of FBXW7 impaired its MCL-1 degradation, leading to chemoresistance to epidermal growth factor receptor (EGFR) inhibitors in NSCLC (Ye et al., 2017). Moreover, decreased FBXW7 levels abrogated the therapeutic sensitivity of chemoradiation therapy (CRT) of esophageal squamous cell carcinoma (ESCC) via targeting MCL-1 (Gombodorj et al., 2018). Likewise, a single-centre retrospective study revealed that silenced FBXW7 strikingly inhibited the progression of oral squamous cell carcinoma patients, as well as the drug sensitivity of CRT (Arita et al., 2017). Overexpression of FBXW7 in pancreatic cancer cells enhanced the response to gemcitabine through an increase in the protein levels of the equilibrative nucleoside transporter 1 (ENT1) which takes up gemcitabine (Hu et al., 2017). It has been shown that oncogenic SRY-box transcription factor 9 (SOX9), which is phosphorylated by GSK3 and subsequently degraded by FBXW7, is involved in cisplatin resistance in medulloblastoma cells (Abshire et al., 2016; Hong et al., 2016). Interestingly, inhibitors of phosphatidylinositol 3-kinase (PI3K)/ AKT/mammalian target of rapamycin (mTOR) pathway could suppress

Fig. 1. The mechanisms of drug resistance to cancer therapy.

using FBPs to overcome chemotherapeutic drug resistance. Role of F-box protein in drug resistance It has been well accepted that 69 FBPs in the human genome have a special structure, i.e. an F-box motif, which is required to select specific substrates to bind and subsequently target them to degradation (Wang et al., 2014). Based on the specific domains, FBPs are characterized as there are several types: 10 FBXW proteins with WD40 repeat domains, 22 FBXL proteins with leucine-rich repeat domains, as well as 37 FBXO proteins with other motifs (Frescas and Pagano, 2008; Welcker and Clurman, 2008). FBPs critically participate in regulation of anticancer drug resistance. In the following paragraphs, we will describe the functions and molecular insights into chemoresistance in various malignancies. FBXW family in drug resistance FBXW7 F-box and WD-40 domain protein 7 (FBXW7), a classic member of the F-box family of proteins, has exclusively been characterized to be an antitumor protein via targeting degradation of its downstream substrates in many human malignancies (Peng and Chen, 2019; Yeh et al., 2018). Furthermore, emerging evidence has revealed that it is also germane to chemotherapy resistance (Peng and Chen, 2019). A study has observed that FBXW7 promoted the degradation of its target substrate snail1, resulting in repression of non-small cell lung cancer (NSCLC) progression, inhibiting the epithelial-mesenchymal transformation (EMT) process and overcoming chemoresistance (Xiao et al., 2018a). FBXW7 overexpression significantly enhanced the chemosensitivity of NSCLC cells to cisplatin via altering the EMT patterns (Yu et al., 2013). Diminished expression of FBXW7 elevated NSCLC carcinogenesis and resistance to gefitinib, which can be reversed by a combined treatment with gefitinib and rapamycin (Xiao et al., 2018b). It has also been unveiled that defective FBXW7 expression is implicated in both poor survival, paclitaxel resistance and increased sensitivity to MS-275, a specific histone deacetylase inhibitor, in NSCLC cells (Yokobori et al., 2014). MS-275 could reverse paclitaxel resistance in these FBXW7-silenced NSCLC cells (Yokobori et al., 2014). Similarly, another group has revealed that EMT and cancer stem-like cells (CSCs) properties are significantly correlated with drug sensitivity in colorectal cancer (CRC) patients (Li et al., 2019b). One study illustrated that zinc finger E-box binding homeobox 2 (ZEB2), one of the key inducers of EMT, is a direct target of FBXW7. Therefore, depletion of FBXW7 triggered EMT and induced chemoresistance (Li et al., 2019b). Moreover, increased FBXW7 expression blocked doxorubicin resistance through decelerating EMT in hepatocellular carcinoma cells, while an inverse result was demonstrated in hepatocellular carcinoma cells with 2

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pancreatic cancer cell lines (Muerkoster et al., 2005a). Moreover, inhibition of β-TrCP1 suppressed growth and survival of human breast cancer cells (Tang et al., 2005), and increased the anti-drug proliferative effects of the chemotherapeutic drugs doxorubicin, tamoxifen, and paclitaxel in breast cancer cells (Tang et al., 2005). Zhang et al., has shown that the Wnt/β-Catenin pathway is implicated in enzalutamide resistance in castration-resistant prostate cancer (Zhang et al., 2018b). Mechanistically, they revealed that pronounced high-expression of βcatenin and androgen receptor (AR) exists in enzalutamide-resistant prostate cancer cells, which is partially mediated by defective β-TrCP ubiquitination (Zhang et al., 2018b). In line with this observation, another study found that CSN6, a subunit of the COP9 signalosome complex, drives the expression of β-catenin in a β-TrCP-dependent manner and subsequently increased EMT in papillary thyroid cancer (PTC) cells (Wen et al., 2018). Herein, PTC cells with CSN6 knockdown were more susceptible to FH535 therapy (Wen et al., 2018). Wang et al., unravelled that berberine inhibited the expression of Cyclin D1 via the β-TrCP-mediated ubiquitin-proteasome axis in human HepG2 hepatoma cells (Wang et al., 2016). Notably, loss of β-TrCP elevated berberine resistance in human hepatoma cells (Wang et al., 2016). An elegant research has established that adenovirus E1A suppressed βTrCP-mediated ubiquitination and proteasome activity of forkhead box O3 (FOXO3a) and inhibitor of NF-κB kinase subunit beta (IKKβ) and consequently upregulated FOXO3a expression, leading to an increased sensitivity of cancer cells to paclitaxel in vitro and in vivo (Su et al., 2011). A disintegrin and metalloproteinase (ADAM) proteases including ADAM10, belong to transmembrane metalloproteases family, which could cleave multiple cell surface proteins (hence known as “sheddases”) and trigger the activation of cellular signalling pathways that are key in tumor progression, such as Notch, EFGR, and the Ephrin (Eph) receptors-regulated pathways (Saha et al., 2019). It has been shown that abrogation of the expression of ADAM10 which is regulated in a β-TrCP-dependent manner, induces cell death in doxorubicin-resistant MCF-7 breast cancer cells (Liu and Chang, 2011). Another study revealed that upregulated β-TrCP1 is involved in elevated NF-κB activity, resulting in chemoresistance towards etoposide (Muerkoster et al., 2005b). These reports clearly demonstrate that β-TrCP plays a role in mediating drug resistance during cancer treatment (Fig. 3).

SOX9 and reverse drug resistance (Abshire et al., 2016). Recently, a study revealed a reciprocal activation between Polo-like kinase-1 (PLK1) and N-Myc (Xiao et al., 2016). PLK1 bound to and phosphorylates the SCFFbw7 ligase, leading to its autopolyubiquitination and degradation, thus counteracting the FBXW7-induced destruction of NMyc, cyclin E and MCL-1 (Gasca et al., 2016; Giraldez et al., 2014). The stabilized N-Myc further increased PLK1 transcriptional activation, forming a positive feedforward regulatory loop that enhanced Mycmediated oncogenesis (Xiao et al., 2016). Thus, PLK1 inhibitors preferentially triggered potent cell apoptotic death of N-Myc-amplified tumor cells and potentiated the therapeutic efficacy of B-cell lymphoma 2 (Bcl2) antagonists (Xiao et al., 2016). The mutation in FBXW7, which is responsible for the development of the T cell acute lymphoblastic leukemia (T-ALL), prevented it from binding to its target substrates NOTCH1, c-Myc and cyclin E (Thompson et al., 2007). Loss of FBXW7 function and consequent overexpression of the c-Myc protein led to a resistance phenotype of most of the T-ALL cell lines to a gamma-secretase inhibitor (Thompson et al., 2007). Collectively, these studies imply a considerable prospect that FBXW7 may serve not only as a potential biomarker for predicting the efficacy of chemotherapy, but also as a promising target to overcome chemoresistance in many cancers (Fig. 2). β-TrCP Accumulated evidence has indicated that β-transducin repeat containing E3 ubiquitin protein ligase (β-TrCP) could play an oncogenic role in multiple tumors. For example, upregulation of β-TrCP1 is observed in more than half of colorectal cancers, which is associated with a dismal prognosis (Ougolkov et al., 2004). In addition, β-TrCP1 is also upregulated in pancreatic cancer (Muerkoster et al., 2005a) and hepatoblastoma tissue samples (Koch et al., 2005). Consistently, β-TrCP2 is elevated in numerous tumor specimens including prostate cancer, gastric cancer, and breast cancer (Fuchs et al., 2004). These reports imply that β-TrCP1/2 upregulation might be a common alteration in human cancers. On the other hand, E3 ligase activity-deficient somatic mutations in β-TrCP1/2 are reported in gastric cancer, which led to gastric cancer development by stabilizing β-catenin (Kim et al., 2007; Saitoh and Katoh, 2001), highlighting the tumor suppressive role of β-TrCP, at least in the gastric cancer setting. Hence, β-TrCP might play either antitumor or oncogenic role in a tissue-specific manner. Elevated levels of β-TrCP1 have been found in chemoresistant

Fig. 2. The potential role of FBXW7 in drug resistance. FBXW7 is responsible for the development of drug resistance via targeting its multiple substrates for degradation in human cancers. 3

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FBXO5 FBXO5, also known as early mitotic inhibitor 1 (EMI1), was found to be involved in drug resistance in human cancer. One elegant study revealed that the potential oncogene evi5 stabilized EMI1 and lead to cyclin accumulation (Eldridge et al., 2006). EMI1 upregulation caused proliferation and genomic instability in cells with p53 deficiency (Lehman et al., 2006). Consistently, EMI1 is highly expressed in malignant tumors compared with benign tumors (Lehman et al., 2007). A study indicated that EMI1 could be a potential therapeutic target in neuroblastoma (Penter et al., 2015). FBXO5 has been known to potentially participate in mantle cell lymphoma pathogenicity (Schraders et al., 2008). Overexpression of EMI1 has been observed in several types of human cancers including ovarian clear cell carcinoma, breast cancer, and lung carcinoma (Gutgemann et al., 2008; Liu et al., 2013; Vaidyanathan et al., 2016; Wang et al., 2018b). Moreover, FBXO5 has been reported to be correlated with worse prognosis in breast cancer patients and other solid tumors (Vaidyanathan et al., 2016; Wang et al., 2018b, a). EMI1 governs proliferation in hepatocellular carcinoma via regulation of S-phase kinase associated protein2 (Skp2) and p27 (Zhao et al., 2013). Knockdown of FBXO5 induced cell apoptosis in lung cancer cells (Wang et al., 2018b). Interestingly, EMI1 controls cell cycle progression via switching from a substrate of APC/CCDH1 to an inhibitor of APC/CCDH1 (Cappell et al., 2018). EMI1 activity is involved in cellular sensitivity to poly ADP-ribose polymerase (PARP) inhibitors via targeting RAD51 for degradation in breast cancer (Marzio et al., 2019). Since breast cancer gene 2 (BRCA2) binds to the DNA repair protein RAD51 and protects it from degradation by EMI1, BRCA-deficient triple-negative breast cancer cells exhibit resistance to PARP inhibitors (Marzio et al., 2019). Depletion of FBXO5 enhanced the sensitivity of human cancer cells to chemotherapeutic and radiation treatment (Shimizu et al., 2013). Collectively, targeted inhibition of FBXO5 might be a novel therapeutic strategy for the treatment of human cancer patients with FBXO5 overexpression, but its oncogenic role warrants further studies with tissue-specific transgenic mouse models.

Fig. 3. The role of β-TrCP in drug resistance development. β-TrCP contributes to drug resistance by targeting the ubiquitination and degradation of its downstream substrates in human malignancies.

FBXO family in drug resistance FBXO4 FBXO4, also termed FBX4, has been known to play a putative role in carcinogenesis. A study has demonstrated that FBXO4 is associated with better overall survival in breast cancer patients (Wang et al., 2019a). FBXO4 targets Pin2 and TRF1 for ubiquitination and degradation, leading to telomere elongation and maintenance in human cells (Lee et al., 2006). FBXO4 targets intercellular adhesion molecule-1 (ICAM-1) for stability, and influences tumor metastasis in breast cancer (Kang et al., 2017). FBXO4 was shown to degrade fragile X protein Fxr1 to inhibit neoplastic progression in head and neck squamous cell carcinoma (Qie et al., 2017). FBXO4 and αB crystallin could target cyclin D1 ubiquitination and decrease cell cycle progression (Lin et al., 2006). Moreover, this group found that mutations in FBXO4 impair dimer formation of the SCF/FBXO4 E3 ligase, leading to cyclin D1 accumulation and tumorigenesis (Barbash et al., 2008). Furthermore, 14-3-3ε has been identified to participate in FBXO4 dimerization and activity, leading to cyclin D1 degradation (Barbash et al., 2011). In addition, alternative splicing variants of FBXO4 impair cyclin D1 degradation in human cancers (Chu et al., 2014). Notably, FBXO4 deficiency triggers BrafV600E-driven melanoma due to the nuclear accumulation of cyclin D1, implying that FBXO4 could act as a barrier to melanoma development (Lee et al., 2013). Consistently, FBXO4 knockout mice developed papilloma when exposed to N-nitrosomethylbenzylamine (NMBA), an esophageal carcinogen (Lian et al., 2015). FBXO4 is also involved in mTORC2-mediated cell growth via GSK3-dependent degradation of cyclin D1 (Koo et al., 2014). Surprisingly, Fbxo4-deficient mice showed no changes in cyclin D1 expression levels, indicating that further investigation is essential to determine whether FBXO4 is an actual ubiquitin ligase for cyclin D1 proteolysis (Kanie et al., 2012). FBXO4 knockdown leads to MCL-1 protein elevation and enhancement of cell survival, as well as resistance to chemotherapeutic drugs in lung cancer, whereas FBXO4 overexpression results in opposite effects (Feng et al., 2017). Another study revealed that combined treatment overcomes resistance to the cyclin dependent kinase 4/6 (CDK4/6) inhibitor, palbocilib, in ESCC with dysregulation of the FBXO4-cyclin D1 axis (Qie et al., 2019). Without a doubt, FBXO4 is involved in tumor progression and anticancer drug resistance.

FBXO6 FBXO6, also known as FBX6 and FBG2, has been demonstrated to be involved in drug resistance during cancer therapy (Cai et al., 2019; Merry et al., 2010; Zhang et al., 2009b). FBXO6 was found to inactivate spindle checkpoint through interaction of mitotic arrest deficient 2 (Mad2) and budding uninhibited by benzymidazol 1-related (BubR1) (Xu et al., 2018). Mitogen-activated protein kinase 1 (MAPK1) promoted cell proliferation and suppressed apoptosis via inhibition of FBXO6 in leukemia cells (Bashanfer et al., 2019). FBXO6 has been reported to be decreased in neuroblastoma, indicating that FBXO6 could be involved in the development of neuroblastoma (Janoueix-Lerosey et al., 2004). Moreover, overexpression of FBXO6 enhanced proliferation of gastric cancer cells and accelerated the cell cycle, suggesting that FBXO6 could maintain the malignant phenotype in gastric cancer (Zhang et al., 2009a). FBXO6 increased tumor cell resistance to certain anti-cancer drugs such as camptothecin through controlling Chk1 degradation, highlighting its possible oncogenic role in human cancers (Zhang et al., 2009b). FBXO6 targets right open reading frame kinase 1 (RIOK1) to induce its ubiquitination and degradation, leading to inhibition of the progression of CRC and gastric cancers (Merry et al., 2010). A study revealed that FBXO6 potentially participated in cisplatin-induced DNA damage in endothelial cells (Li et al., 2018). In line with this finding, FBXO6 has been found to suppress proliferation, induce apoptosis and enhance cellular sensitivity to cisplatin through inhibition of checkpoint kinase 1 (Chk1) in NSCLC (Cai et al., 2019). FBXO7 FBXO7 mutations are mainly associated with Parkinson’s disease 4

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prolonged replication stress (Fugger et al., 2013). Consistently, MUS81 and EME1-depleted cells exhibited enhanced resistance to the cytotoxic effects of replication stress (Fugger et al., 2013). Hence, FBXO18 is required for DNA damage repair which is an important process for genomic instability and cancer development (Sakaguchi et al., 2008). Moreover, FBXO18 helicase regulates homologous recombination (HR) activity to maintain genome integrity (Fugger et al., 2009). Similarly, this FBXO18 helicase regulates HR via disruption of RAD51 filaments (Simandlova et al., 2013). RAD51 overexpression sensitized cells to the DNA damaging agents camptothecin and hydroxyurea. However, depletion of FBXO18 diminished the sensitivity to camptothecin in cells with Rad51 overexpression, suggesting that FBXO18 is involved in drug resistance via regulation of DNA lesions repair (Stanescu et al., 2014). Moreover, deletion of FBXO18 led to hydroxyurea resistance due to inactivation of p53 and impaired DSBs formation (Fugger et al., 2013).

(PD) through the regulation of cell proliferation, cell cycle, mitochondrial function by targeting its substrates (Zhou et al., 2018). FBXO7 overexpression has been found in epithelial tumors other than the normal tissues (Laman et al., 2005). Moreover, FBXO7 overexpression increased the activation of cyclin D/cdk6 and enhanced tumorigenicity in nude mice (Laman et al., 2005). Conversely, downregulation of FBXO7 promoted cell proliferation and shortened the cell cycle at G1 phase in hematopoietic precursor cells, indicating that FBXO7 could play an anti-proliferative role in precursor cells (Meziane el et al., 2011). Moreover, FBXO7 overexpression suppressed proliferation of hematopoietic progenitor cells in a p53-dependent manner. FBXO7 cooperated with p53 loss, thereby leading to lymphomagenesis (Lomonosov et al., 2011). FBXO7 interacted with cellular inhibitor of apoptosis protein 1 (cIAP1) and tumor necrosis factor (TNF) receptor associated factor 2 (TRAF2), leading to reduced RIP1 ubiquitination and inactivation of the NF-κB pathway, suggesting that FBXO7 could act as a negative regulator of NF-κB (Kuiken et al., 2012). One group has reported that the CSN9 signalosome complex blocks FBXO7-involved cereblon degradation, leading to enhanced sensitivity to immunomodulatory drugs including lenalidomide and pomalidomide in multiple myeloma cells (Liu et al., 2019). This study demonstrated that FBXO7 is involved in drug resistance via targeting cereblon in multiple myeloma cells.

FBXO21 FBXO21 targets EP300-interacting inhibitor of differentiation 1 (EID1) for its ubiquitylation and degradation (Watanabe et al., 2015). It was further found that FBXO21 polyubiquitylates EID1 and degrades it in a peptide degron-dependent manner (Zhang et al., 2015). In addition, FBXO21 is required for the activation of apoptosis signal-regulating kinase 1 (ASK1) in antiviral innate response (Yu et al., 2016). A study has found that FBXO21 also targets P-gp for degradation (Ravindranath et al., 2015). The hyaluronic acid (HA) receptor CD44 is highly expressed in multiple carcinomas and contributes to tumor processes including chemoresistance. The HA-bovine serum albumin (BSA) conjugate-cased nanoparticles have been utilized to target cancer treatment in cancer cells with CD44 overexpression (Edelman et al., 2017). Moreover, albumin and HA-coated superparamagnetic iron oxide nanoparticles have been found to entrap and release paclitaxel for potential clinical applications (Vismara et al., 2017). Furthermore, fluorescent HA-serum albumin nanoparticles harbouring paclitaxel displayed cytotoxicity against ovarian cancer cells with CD44 overexpression (Edelman et al., 2019). CD44 impairs FBXO21-mediated proteasomal degradation of P-gp, leading to enhancement of P-gp-dependent multidrug resistance in a CD44 phosphorylation-dependent manner (Ravindranath et al., 2015). Therefore, targeting CD44 could represent an efficient strategy to overcome drug resistance in cancer patients with P-gp overexpression.

FBXO10 FBXO10 has been shown to bind to BCL-2 and trigger its degradation, resulting in cell death (Chiorazzi et al., 2013). In line with this finding, FBXO10 mutations and underexpression have been found in diffuse large B-cell lymphomas (Chiorazzi et al., 2013). FBXO10 deficiency lead to a failure to degrade BCL-2 and subsequently increased BCL-2 levels. BCL-2 upregulation is one reason to acquire ibrutinib resistance in mantle cell lymphoma (MCL) (Li et al., 2016b). Consistently, ABT-199, an inhibitor of BCL-2, synergized with ibrutinib in suppression of cell proliferation in MCL cells (Li et al., 2016b). A study has revealed that cellular stress and lens epithelium-derived growth factor (LEDGF) could increase the expression of FBXO10 (Xu et al., 2014). Therefore, upregulation of FBXO10 could be a useful approach to overcome resistance to ibrutinib in MCL. FBXO15 Pluripotent stem cells can be induced from mouse fibroblasts through overexpression of FBXO15 (Okita et al., 2007), indicating a potential oncogenic role for FBXO15, given the linkage between cellular transformation and differentiation (Hanahan and Weinberg, 2011). Moreover, FBXO15 degrades KBP, an interactor of the mitochondrialassociated kinesin Kif1bα, leading to regulation of mitochondrial biogenesis in mouse differentiating cells (Donato et al., 2017). A study suggested that FBXO15 regulates drug resistance through controlling Pglycoprotein (P-gp) degradation, which is a central mediator of multidrug resistance (Katayama et al., 2013). However, FBXO15−/− mice are viable with no noticeable tumor-associated phenotypes (Tokuzawa et al., 2003), indicating that further studies and transgenic mouse models should be generated to assess its possible oncogenic role.

FBXO22 Wild type p53 promotes transcription of FBXO22, indicating that FBXO22 is a target gene of wild-type p53 (Vrba et al., 2008). FBXO22 targets histone lysine demethylase 4A (KDM4A) for degradation, which leads to regulation of histone H3 lysine 9 and 36 methylation, suggesting a putative function of FBXO22 in development, differentiation, somatic cell reprogramming and disease (Tan et al., 2011). A study has revealed that FBXO22 destabilizes the tumor suppressor Kruppel-like factor 4 (KLF4), a zinc finger transcription factor, through polyubiquitination in HCC cells (Tian et al., 2015). Consistently, increased levels of FBXO22 were documented in human HCC tissues, which is associated with lower levels of KLF4 (Tian et al., 2015). This study demonstrated that FBXO22 promotes HCC progression via controlling KLF4 degradation (Tian et al., 2015). Similarly, it was found that FBXO22 expression is higher in HCC tissues and is correlated with tumor size and vascular invasion as well as survival. Furthermore, FBXO22 enhanced HCC formation and progression via regulation of p21 degradation (Zhang et al., 2019a). FBXO22 increased tumor cell invasiveness and angiogenesis through the HIF-1α and VEGF pathway in malignant melanoma (Zheng et al., 2019). It was further demonstrated that FBXO22 knockdown suppressed tumor progression and metastasis in vivo, indicating that FBXO22 might be developed as a potential target for the treatment of melanoma patients (Zheng et al.,

FBXO18 FBXO18, also known as FBH1, FBX18, and FLJ14590, has been defined to participate in carcinogenesis. FBXO18 was shown to play a key role as a DNA helicase in mediating DNA double-strand break (DSB) formation following replication inhibition (Fugger et al., 2013). Cells with FBXO18 depletion exhibited resistance to hydroxyurea, and have impaired p53 activation, and decreased DNA DSB formation (Fugger et al., 2013). Furthermore, FBXO18 worked together with the MUS81 endonuclease and enhanced endonucleolytic DNA cleavage after 5

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FBXO31 phosphorylation governs proteolysis of FBXO31 by the APC/C coactivators CDH1 and cell division cycle 20 (CDC20) (Choppara et al., 2018). FBXO31 overexpression is associated with tumor invasion and tumor stage in ESCC (Kogo et al., 2011; Liu et al., 2018). ESCC patients with high levels of FBXO31 have a poor prognosis (Kogo et al., 2011). Moreover, FBXO31 overexpression deregulates MAPK p38a and JNKinduced apoptosis in ESCC (Liu et al., 2018). Knockdown of FBXO31 sensitized cells to cisplatin treatment in ESCC, revealing that FBXO31 plays a regulatory role in drug resistance (Liu et al., 2018). Consistently, miR-29c was found to override cells 5-FU resistance, which is due to inhibition of FBXO31 and subsequent activation of p38 MAPK in ESCC, indicating that FBXO31 is involved in 5-FU resistance (Li et al., 2019a).

2019). FBXO22 also exhibited a dual role in breast cancer carcinogenesis and metastasis. Specifically, FBXO22 facilitated proliferation and colony formation of mammary tumor cells, whereas FBXO22 inhibited EMT, cell migration, and invasion via targeting Snail degradation (Sun et al., 2018). Moreover, FBXO22 is overexpressed in primary mammary tumors and is correlated with clinical outcomes (Sun et al., 2018). Another study validated that selective estrogen receptor modulators (SERMs) activity is governed by FBXO22-dependent lysine demethylase 4B (KDM4B) degradation in mammary tumors (Johmura et al., 2018). Recently, FBXO22 was shown to inhibit cell invasion and metastasis via targeting human homolog of mouse double minutes 2 (HDM2) in breast cancer (Bai et al., 2019). FBXO22 stimulated cell growth via regulation of liver kinase B1 (LKB1) ubiquitination and degradation in lung cancer (Zhu et al., 2019). FBXO22 expression is increased in lung cancer tissues and is correlated with poor prognosis in lung cancer patients (Zhu et al., 2019). Recently, Pagano’s group discovered that Nrf2 promotes lung cancer metastasis via suppression of the heme- and FBXO22-involved degradation of the transcription factor BTB and CNC homology 1 (Bach1) (Lignitto et al., 2019). Bach1 is often expressed in a majority of mammalian tissues and serves as a transcriptional suppressor of targeted genes to control cellular and pathological processes (Zhang et al., 2018a). In renal cell carcinoma (RCC) tissues, FBXO22 expression levels were very low and this was associated with tumor size, TNM stage and worse survival. FBXO22 suppressed cell motility and EMT through inhibition of both metalloproteinase-9 (MMP-9) and VEGF expression in RCC (Guo et al., 2019). CD147 (Basigin), a transmembrane glycoprotein of the immunoglobulin superfamily, was found to contribute to chemoresistance of cancer cells in a variety of human malignancies (Grass et al., 2014). One study found that FBXO22 triggers CD147 ubiquitination and degradation, leading to reversal of cisplatin resistance in cancer cells (Wu et al., 2017).

FBXO32 FBXO32 promoter methylation, leading to repression of FBXO32 expression at both the mRNA and protein levels, is observed in ESCC tumor specimens which is correlated with survival in ESCC patients (Guo et al., 2014). FBXO32 is a predictor of node metastasis in patients with oral cancer (Mendez et al., 2011). FBXO32 targets KLF4 for degradation and inhibits the development of breast cancer (Zhou et al., 2017). Gemcitabine-mediated DNA damage response is regulated by FBXO32 in pancreatic cancer (Yang et al., 2018). One study has revealed that DZNep, an inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH) and enhancer of zester homolog 2 (EZH2), induced apoptosis in cancer cells in part through upregulation of FBXO32 in breast cancer cells (Tan et al., 2007). Another study showed that combination of DZNep and histone deacetylase (HADC) inhibitor panobinostat synergistically induced apoptosis in AML cells (Fiskus et al., 2009). FBXO32 has been reported as a tumor suppressor and a transforming growth factor beta (TGF-β)/Smad family member 4 (SMAD4) target gene (Chou et al., 2010). In support of this notion, FBXO32 promoter methylation correlated with poor prognosis in human ovarian cancer, and re-introduction of FBXO32 markedly inhibited cell proliferation and sensitized cells to chemotherapeutic drugs such as cisplatin (Chou et al., 2010). FBXO32 negatively regulates EMT in cisplatin-resistant urothelial carcinoma (UC) cells (Tanaka et al., 2016). FBXO32 dysregulation increases the expression of the mesenchymal markers Snail and vimentin and decreases E-cadherin levels in cisplatin resistant UC cells. Downregulation of MyoD expression, a substrate of FBXO32, leads to increased E-cadherin and decreased Snail and vimentin in platinum-resistant UC cells (Tanaka et al., 2016). EZH2, a histone-lysine N-methyltransferase that mediates histone methylation and transcriptional repression, participates in gastric cancer cell resistance to 5-FU via suppression of FBXO32 expression (Wang et al., 2018a). FBXO32 expression is downregulated in 5-FU-resistant cells in gastric cancer. Knockdown of FBXO32 enhanced 5-FU cytotoxicity in gastric cancer cells which acquired a prior 5-FU resistance (Wang et al., 2018a). However, further studies are warranted to define the role of FBXO32 in drug resistance.

FBXO31 FBXO31 is downregulated in breast cancer specimens compared with normal breast epithelium (Kumar et al., 2005). FBXO31 is associated with poor survival in breast cancer patients (Wang et al., 2019a). Ectopic expression of FBXO31 suppressed proliferation and induced cell cycle arrest at the G1 phase in breast cancer cells (Kumar et al., 2005). FBXO31 exerts its tumor suppressive function via proteasome degradation of cyclin D1 after genotoxic stress (Santra et al., 2009). Similarly, decreased expression of FBXO31 has been observed in HCC cell lines and specimens, and overexpression of FBXO31 attenuated proliferation of HCC cells via targeting of cyclin D1 for degradation (Huang et al., 2010). One study revealed that FBXO31 targets Cdt1 for degradation in the G2 phase thereby blocking re-replication (Johansson et al., 2014). Another study has reported that FBXO31 inhibits the p38 MAPK signalling pathway via targeting K48-dependent ubiquitination and proteolysis of MAPK kinase 6 (MKK6) in response to stress (Liu et al., 2014). Additionally, FBXO31 targets mouse double minute 2 (MDM2) for degradation, thereby enhancing p53-triggered growth arrest after DNA damage (Malonia et al., 2015). In gastric cancer tissues, the expression of FBXO31 mRNA and protein is down-regulated and is associated with tumor size, tumor grade and prognosis (Zhang et al., 2014). Moreover, FBXO31 exerts its anti-tumor activity in gastric cancer cells, which is negatively regulated by miR-20a and miR-17 (Zhang et al., 2014). Zou et al., found that FBXO31 inhibits EMT via regulation of Snail1 degradation in gastric cancer (Zou et al., 2018). MiR-210 has also been found to inhibit the expression of FBXO31 in breast cancer, leading to mammary tumor progression (Liu et al., 2016). Ectopic expression of FBXO31 facilitated cell proliferation, invasion and metastasis in lung cancer cells, suggesting that FBXO31 could act as an oncoprotein in lung cancer (Huang et al., 2015). In line with this report, FBXO31 expression is highly expressed in lung cancer specimens and is correlated with tumor size, tumor stage and metastasis (Huang et al., 2015). Akt- and ataxia-telangiectasia mutated (ATM)-dependent

FBXO45 FBXO45 was originally found to be induced by estrogen in breast cancer cells (Yoshida, 2005). Mice with FBXO45 depletion have been reported to die soon after birth due to respiratory distress and impairment of neuronal development (Saiga et al., 2009). FBXO45 is downregulated and correlated with tumor progression and poor prognosis in gastric cancer (Kogure et al., 2017). FBXO45 governs synaptic activity via induction of degradation of Munc 13-1 at the synapse (Tada et al., 2010). FBXO45 can target the p73 transcription factor for ubiquitination and subsequent degradation (Peschiaroli et al., 2009). FBXO45 controls cancer cell survival through targeting Par-4 for proteasome degradation (Chen et al., 2014a; Wang and Wei, 2014). Moreover, overexpression of FBXO45 has been observed in lung cancer and is 6

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Fig. 4. The role of Skp2 in regulation of drug resistance. Skp2 overexpression leads to the development of drug resistance due to the enhanced degradation of multiple substrates of Skp2 and activation of several signalling pathways in various cancers.

correlated with shorter survival (Wang et al., 2018b). m6A methylation was correlated with the RP11 upregulation via increasing its nuclear accumulation. Clinical data showed that m6A governed the expression of RP11, the latter of which further regulated Siah1-Fbxo45/Zeb1, thereby facilitating CRC development (Wu et al., 2019). FBXO45 is also involved in drug resistance in human cancer therapy; loss of FLASH resulted in ZEB1 ubiquitination and degradation by FBXO45 and SIAH1, leading to reversal of both EMT and chemotherapy resistance to gemcitabine in pancreatic cancer cells (Abshire et al., 2016). Therefore, it has been proposed that this FLASH-ZEB1 interaction might abrogate degradation of ZEB1, an EMT inducer, in cancer cells, suggesting that FLASH might be a promising target to demolish EMT progression in tumor cells (Abshire et al., 2016). Moreover, PAF binds to FBXO45 and rescues cancer cell apoptosis induced by Par-4, which could overcome drug resistance via inhibition of FBXO45 in cancer cells (Hebbar et al., 2017).

cells (Ishii et al., 2004). It has been shown that the oral anti-diabetic troglitazone could impair Skp2 expression and subsequently elevate p27, which finally arrested human hepatoma cells cycle progression (Koga et al., 2003). Upregulation of Skp2 decreased cell sensitivity to troglitazone in hepatocellular carcinomas (Koga et al., 2003). Similarly, another study verified that decreased p27 expression is germane to chemoresistance in human malignancies (Ungermannova et al., 2013). Interestingly, Skp2 interacted with Cks1 and induced p27 degradation, which is associated with drug resistance (Ungermannova et al., 2013). High levels of Skp2 increased actinomycin D resistance in gastric carcinoma via decreased accumulation of p27 (Masuda et al., 2002). A novel preclinical inhibitor which interfered with SCF (Skp2) ligase function, resulted in high level of Skp2 substrates, consequently sensitizing mice harboring multiple myeloma (MM) tumors to dexamethasone, doxorubicin and melphalan, and bortezomib (Chen et al., 2008). Clinically, preoperative high Skp2 expression was found to be correlated with resistance to cyclophosphamide/ adriamycin/ 5-FU (CAF) in primary breast cancer cells (Davidovich et al., 2008). Likewise, another study demonstrated that Skp2 expression is attenuated, resulting in subsequent p27 stabilization, multidrug resistance associated protein 1 (MRP1/ABCC1) deficiency, inhibition of cell cycle progression, and restoration of sensitivity to chemotherapeutic drugs including adriamycin, daunorubicin, and arabinosylcytosine (Ara C) in leukemia cells (Xiao et al., 2009). One research group unveiled that loss of Skp2 blocked Akt activation and enhanced cellular sensitivity to Herceptin in HER2-overexpressing breast cancer cells, whereas elevated Skp2 exhibited the opposite effect (Chan et al., 2012). USP10 is a deubiquitinase of Skp2 to maintain the stabilization of Skp2, which promotes cell proliferation in CML cells (Liao et al., 2019). Downregulation of USP10 inhibits cell proliferation in both imatinib-sensitive and -resistant cells (Liao et al., 2019). Targeting USP10/Skp2 could be helpful to overcome imatinib resistance in patients with CML. Arsenic trioxide enhances cell chemosensitivity to gemcitabine via suppression of Skp2 in pancreatic cancer cells (Gao et al., 2019). Knockdown of Skp2 expression restored cellular susceptibility to rapamycin in vitro and in vivo (Totary-Jain et al., 2012). EMT was shown to facilitate acquired drug resistance in cancer cells. Overexpression of Skp2 is associated with methotrexate resistance in osteosarcoma cells due to the induction of EMT (Ding et al., 2018b). Abrogation of Skp2 can partly restore paclitaxel sensitivity, which was mediated by EMT (Yang et al., 2014). Depletion of

The role of the FBXL family in anticancer drug resistance FBXL1 FBXL1, also named Skp2, has been extensively investigated in tumorigenesis and drug resistance. For instance, a study has shown that inhibition of Skp2 leads to cell sensitivity to paclitaxel in lung cancer cells via decreased expression of MAD2 and increased phosphorylated retinoblastoma (pRB) and p27 (Huang et al., 2017). AMPK phosphorylates Skp2 and subsequently activates Akt, leading to oncogenic processes and cellular resistance to anti-EGFR treatment (Han et al., 2018). OCT-4 increases tamoxifen resistance because Nkx3-1, a repressor of OCT-4, is degraded by Skp2 in breast cancer cells, indicating that Skp2 is involved in tamoxifen resistance (Bhatt et al., 2016). Moreover, overexpression of Skp2 is observed in paclitaxel-resistant prostate cancer cells, and inhibition of Skp2 sensitized cell sensitivity to paclitaxel in prostate cancer cells (Byun et al., 2018a). One elegant study revealed that a novel selenonucleoside (4'-selenofuranosyl-2,6-dichloropurine, LJ-2618), which promotes Skp2 degradation and leads to high levels of p27 in PC-3 cells, increased the sensitivity of these paclitaxel-resistant prostate cancer cells to paclitaxel (Byun et al., 2018b). Increased Skp2 expression promoted cell cycle progression via preventing the expression of p27, cyclin E, and p21, and provoked chemoresistance to camptothecin and cisplatin in lung adenocarcinoma 7

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Emerging evidence shows that FBXL5 is associated with tumor development and progression. G-protein-coupled estrogen receptor (GPER) inhibits cell migration and invasion through FBXL5-targeted degradation of Snail in osteosarcoma cells (Wang et al., 2019b). FBXL5 is highly expressed in colon cancer tissues, facilitates proliferation and tumorigenesis and suppresses apoptosis via regulation of the phosphatase and tensin homolog (PTEN)/PI3K/Akt pathway in colon cancer (Yao et al., 2018). FBXL5 attenuated cell migration and invasion via inhibition of Snail1 in gastric cancer (Wu et al., 2015). Silencing FBXL5 increased E-cadherin expression in cancer cells (Dragoi et al., 2014). One study showed that miR-1306-3p inhibited the expression of FBXL5 and subsequently suppressed Snail proteolysis, leading to upregulation of Snail, which promotes tumor metastasis in HCC (He et al., 2018). Another study revealed that depletion of FBXL5 and B-cell translocation gene 3 (BTG3) increased cell invasiveness and cisplatin chemoresistance in cervical cancer (Xiong et al., 2017). Moreover, a critical EMT inducer inhibitory ankyrin-repeat, SH3-domain and proline-rich region containing protein (iASPP) enhanced cisplatin resistance via targeting of FBXL5 and BTG3 with miR-20a in cervical cancer (Xiong et al., 2017). Additionally, FBXL5 deletion increased cisplatin resistance by activation of Erk and p38 in gastric cancer cells (Wu et al., 2016). FBXL5 binds to Rho GDP dissociation inhibitor beta (RhoGDI2) and reduces RhoGDI2-mediated gastric cancer cell resistance to cisplatin (Wu et al., 2016). FBXL5 expression is suppressed after iron depletion and γ-irradiation, resulting in Snail1 stabilization. This study indicated that radiotherapy increases Snail1 via inhibition of FBXL5 (VinasCastells et al., 2014). FBXL5 targets human single strand DNA binding protein 1 (hSSB1) for ubiquitination and destruction, leading to activation of ATM and enhanced radiosensitivity and chemosensitivity in lung cancer (Chen et al., 2014b).

ribosomal RNA genes, leading to suppression of cell size and cell proliferation (Frescas et al., 2007). In agreement with this finding, low expression levels of FBXL10 were documented in aggressive brain tumors, indicating that FBXL10 could have an anti-tumor activity (Frescas et al., 2007). FBXL10 is highly overexpressed in triple negative breast cancers and is highly correlated with post-treatment relapse (Kottakis et al., 2014). Moreover, FBXL10 governs self-renewal via regulation of polycomb complexes PRC1 and PRC2 in breast cancer stem cells (Kottakis et al., 2014). In addition, overexpression of FBXL10 is observed in diffuse large B-cell lymphoma (DLBCL) tissues, and knockdown of FBXL10 attenuates cell proliferation in vitro and tumor growth in mice (Zhao et al., 2018). Mechanistically, FBXL10 facilitates DLBCL development via regulation of DUSP6 and activation of the ERK1/2 pathway (Zhao et al., 2018). Downregulation of FBXL10 leads to suppression of cell proliferation and enhances autophagy by inhibition of pAkt and its targets mTOR and p70S6K as well as increased pERK in gastric cancer cells (Zhao et al., 2017). FBXL10 negatively regulates cell proliferation via targeting c-Fos for proteolysis after mitogenic stimulation (Han et al., 2016). Mice with overexpression of FBXL10 in hematopoietic stem cells (HSCs) exhibited B-lymphoid leukemia via activation of metabolism and promotion of neuron-specific gene family member 2 (Nsg2) (Ueda et al., 2015). FBXL10 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) tissues, which is associated with tumor grade, tumor stage, and metastasis (Tzatsos et al., 2013). FBXL10 overexpression in combination with Kras12D facilitated PDAC development in mice (Tzatsos et al., 2013). One study found that FBXL10 is a breast cancer anti-estrogen resistance (BCAR) gene in breast cancer, implying that FBXL10 is involved in tamoxifen therapy response (van Agthoven et al., 2010). Downregulation of FBXL10 sensitized cells, hence inducing TRAIL-mediated apoptosis, whereas upregulation of FBXL10 inhibited TRAIL-triggered apoptosis via regulation of the c-Fos/c-FLIP pathway (Ge et al., 2011). Yan et al., reported that miR-146b increased chemosensitivity to cisplatin and paclitaxel, and enhanced cell proliferation via suppression of FBXL10 in ovarian cancer (Yan et al., 2018). Unexpectedly, miR-146b-mediated inhibition of FBXL10 repressed cell migration and invasion in ovarian cancer (Yan et al., 2018).

FBXL7

FBXL17

FBXL7 inhibits cell proliferation and induces cell cycle arrest at the G2/M phase via targeting ubiquitination and degradation of Aurora A in transformed murine lung epithelia (Coon et al., 2012). One pathwaybased expression array revealed that FBXL7 plays an important role in ovarian cancer survival (Kim et al., 2012). FBXL7 has been identified to be a core transcription factor in tumorigenesis of lung cancer (Liu et al., 2017). FBXL7 regulates Survivin expression levels via the ubiquitin proteasome pathway. Aurora Kinase A (AURKA) increases Survivin protein levels via downregulation of FBXL7 and subsequent inhibition of Survivin degradation, leading to enhanced drug resistance (Kamran et al., 2017). This study indicated that FBXL7 contributes to drug resistance via targeting Survivin expression. In addition, FBXL7 levels were increased in both paclitaxel-resistant cells and in patients with ovarian cancer (Chiu et al., 2018). FBXL7 overexpression is associated with paclitaxel resistance and poor prognosis in ovarian cancer patients. Moreover, downregulation of FBXL7 increased ovarian cancer cell sensitivity to paclitaxel (Chiu et al., 2018). Therefore, FBXL7 levels might be a potential biomarker for selecting paclitaxel therapy in individual ovarian cancer patients.

FBXL17 governs activation of the NRF2 oxidative stress pathway through turnover of Bach1 (Tan et al., 2013). FBXL17 can target suppressor of fused (Sufu), a tumor suppressor in the hedgehog signaling pathway, to inactivate glioma-associated oncogene homolog (Gli) transcription factor, for proteolysis in medulloblastoma cells (Raducu et al., 2016). FBXL17 depletion provoked an impaired cell proliferation and tumor growth via upregulation of Sufu and subsequent inhibition of Gli in medulloblastoma (Raducu et al., 2016). FBXL17 has been reported to promote human ribonucleotide reductase M2 expression that is associated with multidrug resistance in breast cancer cells (Xiao et al., 2008), indicating an oncogenic role for FBXL17 in breast cancer. Further investigation is needed to determine the role of FBXL17 in drug resistance in human cancers.

Skp2 blocked DNA repair mediated by ATM protein kinase and sensitized cisplatin-resistant mantle cell lymphoma cells (Yan et al., 2019). Hence, Skp2 overexpression contributed to drug resistance in human cancer therapy (Fig. 4). FBXL5

F-box proteins as therapeutic targets A recent study revealed that loss of FBXW7 in cancer cells promotes resistance to paclitaxel and ABT-737 (Inuzuka et al., 2011; Wertz et al., 2011). Thus, upregulation of FBXW7 could reverse drug resistance to certain therapeutic drugs including the abovementioned drugs (Inuzuka et al., 2011; Wertz et al., 2011). Therefore, development of inhibitors for upstream regulatory proteins to activate FBW7 activity, or for downstream oncoproteins, could be a viable therapeutic approach. A selenonucleoside LJ-2618 has been found to overcome paclitaxel resistance via induction of Skp2 degradation in prostate cancer cells (Byun et al., 2018a). An extract from the fungus Antrodia cinnamomea

FBXL10 FBXL10, also known as JHDM1B, Ndy1, or KDM2B, is originally characterized as the H3K36 demethylase to control cell proliferation and senescence via regulation of p15 (He et al., 2008; Sanchez et al., 2007). FBXL10 acts as a nucleolar protein to inhibit transcription of 8

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Table 1 F-box proteins and their impact on cancer chemoresistance. F-box protein

Substrate protein

Cancer types

Chemotherapeutic drugs

FBP Functions

FBXW7

ZEB2, P53, CRY2, MCL-1 MCL-1 MCL-1

CRC CRC ESCC GC HCC MC NSCLC NB T-ALL PC BC PC PrC PTC HCC BC BC LC ESCC BC BC, GL, CRC, LC, HNC, OS. LC, BC NSCLC MM MCL CRC, FS OS BC HCC, NSCLC ESCC OC UC GC PC LC, BC, PrC LC BC BC PrC LC HCC GC MM LE CML PC Human Cancers OS LY CC GC LC

Doxorubicin, Oxaliplatin, Regorafenib, Sorafenib, Regorafenib

Chemosensitivity Chemosensitivity Chemoradiation sensitivity Chemosensitivity Chemosensitivity Chemosensitivity Chemosensitivity Chemosensitivity Chemosensitivity Chemosensitivity Chemoresistance Chemoresistance Chemosensitivity Chemosensitivity Chemosensitivity Chemosensitivity Chemoresistance Chemosensitivity Chemosensitivity Chemoresistance Chemoresistance Chemoresistance Chemosensitivity Chemoresistance Chemosensitivity Chemosensitivity Chemoresistance Chemosensitivity Chemosensitivity Chemoresistance Chemosensitivity Chemosensitivity Chemosensitivity Chemosensitivity Chemoresistance Chemoresistance Chemoresistance Chemoresistance Chemoresistance Chemoresistance Chemoresistance Chemoresistance Chemoresistance Chemoresistance Chemoresistance Chemoresistance Chemoresistance Chemoresistance Chemoresistance Chemosensitivity Chemosensitivity Chemosensitivity, Radiosensitivity Chemosensitivity Chemoresistance Chemoresistance Chemoresistance

SOX9 Snail1, MCL-1, N-Myc N-Myc c-Myc β-TrCP1 β-TrCP

FBXO4 FBXO5 FBXO6 FBXO7 FBXO10 FBXO15 FBXO18 FBXO21 FBXO22 FBXO31 FBXO32

β-catenin, AR β-catenin Cyclin D1 Sp1 FOXO3a MCL-1 Cyclin D1 RAD51 Chk1 Chk1 Cereblon BCL-2 P-gp RAD51, p53 P-gp CD147 MAPk p38, JNK MyoD

FBXO45

ZEB1 Par-4

FBXL1 Nkx3-1

P27 P27 P27 P27

FBXL5 RhoGDI2 hSSB1 FBXL7 FBXL10 FBXL17

Survivin

GC OC OC BC

Cisplatin, Docetaxel + Cisplatib+5-Fu regimen, Doxorubicin Cisplatin Cisplatin, Gefitinib, Taxol, Erlotinib, EGFR inhibitor, Gamma-secretase inhibitor Gemcitabine Doxorubicin, Tamoxifen, Paclitaxel Etoposide Enzalutamide FH535 Berberine Doxorubicin Paclitaxel Cisplatin, Paclitaxel Palbocilib PARP inhibitors Doxorubicin Camptothecin, Cisplatin Lenalidomide, Pomalidomide Ibrutinib Vincristine Camptothecin, Hydroxyurea Cisplatin Cisplatin, 5-FU Cisplatin Platinum 5-FU Gemcitabine Paclitaxel Paclitaxel Tamoxifen, Cyclophosphamide/Adriamycin/5-FU (CAF), Paclitaxel Herceptin Paclitaxel Camptothecin, Cisplatin, AF1478 Teglitazone Acyinom Dexamethasone, Doxorubicin, Melphalan, Dortezomib Adriamycin, Daunorubicin, Arabinosylcytosine (Ara C) Imatinib Gemcitabine Rapamycin Methotrexate Cisplatin Cisplatin Cisplatin Etoposide Doxorubicin Paclitaxel Cisplatin, Paclitaxel Multidrug resistance

BC: breast cancer; CC: cervical cancer; CML: chronic myeloid leukemia; CRC: colorectal cancer; ESCC: esophageal squamous cell carcinoma; FS: fibrosarcoma; GC: gastric cancer; GL: glioma; HCC: hepatocellular carcinoma; HNC: head and neck cancer; LC: lung cancer; LE: leukemia; LY: lymphoma; MC: medulloblastoma; MCL: mantle cell lymphoma; ME: Melanoma; MM: multiple myeloma; NSCLC: non-small cell lung cancer; NB: Neuroblastoma; OS: osteosarcoma; OC: ovarian cancer; PC: pancreatic cancer; PrC: prostate cancer; PTC: papillary thyroid cancer; T-ALL: T-cell acute lymphoblastic leukemia; UC: urothelial carcimoma.

anti-cancer treatments by targeting the responsible FBPs or FBP signalling pathways in specific tissues. Taken together, targeting FBPs could be a promising strategy to overcome drug resistance.

suppressed tumor cell growth via inhibition of Skp2 by upregulating miR-21-5p, miR-26-5p, and miR-30-5p in tamoxifen-resistant breast cancer cells (Lin et al., 2018). Flavokawain A as a Kava chalcone sensitized breast cancer cells (with HER2 overexpression) to herceptin partly through inhibition of Skp2 (Jandial et al., 2017). The Skp2 inhibitor DT204 has been found to overcome resistance to the proteasome inhibitor bortezomib in MM cells (Malek et al., 2017). On the basis of the fact that many FBPs have various functions in different cancer types, it is reasonable to design personalized medicine as efficacious

Conclusions FBPs play an essential role in the development of anticancer drug resistance through degradation of their downstream substrates (Table 1). It is necessary to mention that less than 20 FBPs were found 9

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to be involved in chemotherapeutic drug resistance. Most of studies focused on role of several FBPs in drug resistance such as FBXW7, βTrCP, and Skp2. Therefore, among the 69 FBPs, whether other FBPs participate in drug resistance is yet unknown, and warrants further studies. The molecular mechanism underlying FBPs-mediated drug resistance or sensitivity needs to be further elucidated. One FBP could enhance drug resistance or sensitivity in various cancer types, suggesting that targeting FBPs as a strategy might be a context-specific manner. Due to the fact that a single FBP targets multiple key substrates, one should consider this point if FBPs are to become therapeutic targets aimed to overcome drug resistance. Altogether, FBPs could be potential druggable targets to enhance tumor cell sensitivity to cancer therapy.

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Authors' contributions LY, ML, YGA and SP searched the literature regarding FBPs and drug resistance; LY, ML, and SP made the figures and tables. LY and ML wrote the manuscript. ZW, YGA and XZ edited and approved the manuscript. All authors read and approved the final manuscript. Declaration of Competing Interest The authors declare that they have no competing interests. Acknowledgments This work was supported by the Science and Technology Planning Project of Wenzhou City (No. Y20180082 and ZS2017006) and the Research Fund for Lin He’s Academician Workstation of New Medicine and Clinical Translation. References Abshire, C.F., Carroll, J.L., Dragoi, A.M., 2016. FLASH protects ZEB1 from degradation and supports cancer cells’ epithelial-to-mesenchymal transition. Oncogenesis 5, e254. Amawi, H., Sim, H.M., Tiwari, A.K., Ambudkar, S.V., Shukla, S., 2019. ABC transportermediated multidrug-resistant Cancer. Adv. Exp. Med. Biol. 1141, 549–580. Arita, H., Nagata, M., Yoshida, R., Matsuoka, Y., Hirosue, A., Kawahara, K., Sakata, J., Nakashima, H., Kojima, T., Toya, R., Murakami, R., Hiraki, A., Shinohara, M., Nakayama, H., 2017. FBXW7 expression affects the response to chemoradiotherapy and overall survival among patients with oral squamous cell carcinoma: a singlecenter retrospective study. Tumour Biol. 39, 1010428317731771. Assaraf, Y.G., Brozovic, A., Goncalves, A.C., Jurkovicova, D., Line, A., Machuqueiro, M., Saponara, S., Sarmento-Ribeiro, A.B., Xavier, C.P.R., Vasconcelos, M.H., 2019. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resist. Updat. 46, 100645. Bai, J., Wu, K., Cao, M.H., Yang, Y., Pan, Y., Liu, H., He, Y., Itahana, Y., Huang, L., Zheng, J.N., Pan, Z.Q., 2019. SCF(FBXO22) targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis. Proc. Natl. Acad. Sci. U. S. A. 116, 11754–11763. Barbash, O., Lee, E.K., Diehl, J.A., 2011. Phosphorylation-dependent regulation of SCF (Fbx4) dimerization and activity involves a novel component, 14-3-3varepsilon. Oncogene 30, 1995–2002. Barbash, O., Zamfirova, P., Lin, D.I., Chen, X., Yang, K., Nakagawa, H., Lu, F., Rustgi, A.K., Diehl, J.A., 2008. Mutations in Fbx4 inhibit dimerization of the SCF(Fbx4) ligase and contribute to cyclin D1 overexpression in human cancer. Cancer Cell 14, 68–78. Bashanfer, S.A.A., Saleem, M., Heidenreich, O., Moses, E.J., Yusoff, N.M., 2019. Disruption of MAPK1 expression in the ERK signalling pathway and the RUNX1RUNX1T1 fusion gene attenuate the differentiation and proliferation and induces the growth arrest in t(8;21) leukaemia cells. Oncol. Rep. 41, 2027–2040. Bhatt, S., Stender, J.D., Joshi, S., Wu, G., Katzenellenbogen, B.S., 2016. OCT-4: a novel estrogen receptor-alpha collaborator that promotes tamoxifen resistance in breast cancer cells. Oncogene 35, 5722–5734. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A., Jemal, A., 2018. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424. Byun, W.S., Jin, M., Yu, J., Kim, W.K., Song, J., Chung, H.J., Jeong, L.S., Lee, S.K., 2018a. A novel selenonucleoside suppresses tumor growth by targeting Skp2 degradation in paclitaxel-resistant prostate cancer. Biochem. Pharmacol. 158, 84–94. Byun, W.S., Jin, M., Yu, J., Kim, W.K., Song, J., Chung, H.J., Jeong, L.S., Lee, S.K., 2018b. A novel selenonucleoside suppresses tumor growth by targeting Skp2 degradation in paclitaxel-resistant prostate cancer. Biochem. Pharmacol. 158, 84–94. Cai, L., Li, J., Zhao, J., Guo, Y., Xie, M., Zhang, X., Wang, L., Tian, H., Li, A., Li, Q., Miao,

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