Pleiotropic roles in cancer biology for multifaceted proteins FKBPs

BBAGEN-28132; No. of pages: 8; 4C: Biochimica et Biophysica Acta xxx (2015) xxx–xxx

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Review

Pleiotropic roles in cancer biology for multifaceted proteins FKBPs☆ Simona Romano a,1, Anna D’Angelillo a,b,1, Maria Fiammetta Romano a,⁎ a b

Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples, Italy Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy

a r t i c l e

i n f o

Article history: Received 24 September 2014 Received in revised form 5 January 2015 Accepted 6 January 2015 Available online xxxx Keywords: FK506 binding protein Peptidyl-prolyl-isomerase Tumorigenesis Cancer

a b s t r a c t Background: FK506 binding proteins (FKBP) are multifunctional proteins highly conserved across the species and abundantly expressed in the cell. In addition to a well-established role in immunosuppression, FKBPs modulate several signal transduction pathways in the cell, due to their isomerase activity and the capability to interact with other proteins, inducing changes in conformation and function of protein partners. Increasing literature data support the concept that FKBPs control cancer related pathways. Scope of the review: The aim of the present article is to review current knowledge on FKBPs roles in regulation of key signaling pathways associated with cancer. Major conclusions: Some family members appear to promote disease while others are protective against tumorigenesis. General significance: FKBPs family proteins are expected to provide new biomarkers and small molecular targets, in the near future, increasing diagnostic and therapeutic opportunities in the cancer field. This article is part of a Special Issue entitled Proline-Directed Foldases: Cell Signaling Catalysts and Drug Targets. © 2015 Elsevier B.V. All rights reserved.

1. Introduction Accumulating evidence [1–6], in the last decade, on anti-cancer effects of immunosuppressant agents, have provided important insights into the functions of these compounds in oncogenic pathways, which gained, for rapamycin and derivatives, a relevant position in the armamentarium of cancer therapeutics [7]. Rapamycin and FK506 are produced respectively by Streptomyces hygroscopicus [8] and Streptomyces tsukabaensis [9] and widely used for prevention of allograft rejection after organ transplantation. Both compounds form complexes with the FK506 binding protein 12 (FKBP12). Particularly, rapamycin forms a ternary complex with FKBP12 and the FKBP12/rapamycin binding (FRB) domain of mammalian target of rapamycin (mTOR), being an allosteric inhibitor of mTOR complex 1 [10]. Rapamycin/FKBP12 inhibits mTOR by directly blocking substrate recruitment, restricting access to enzyme active-site. FK506 in complex with FKBP12 targets calcineurin phosphatase, resulting in inhibition of recruitment of substrates for efficient dephosphorylation. Both mTOR [1–3] and calcineurin [4–6] are deregulated in various cancers and responsible for competitive growth advantage, metastatic competence, and therapy resistance ☆ This article is part of a Special Issue entitled Proline-Directed Foldases: Cell Signaling Catalysts and Drug Targets. ⁎ Corresponding author at: Department of Molecular Medicine and Medical Biotechnologies, Federico II University, via Pansini, 5. 80131. Naples, Italy. Tel.: + 39 0817463125; fax: +39 0817463205. E-mail addresses: mariafi[email protected], [email protected] (M.F. Romano). 1 Equal contribution.

[1–6]. FKBP12 is the leading member of a subfamily of proteins that, together with cyclophilins, belong to the family of immunophilins [11]. This protein subfamily is characterized by a highly conserved domain of binding to the natural compounds FK506 and rapamycin, termed FK. FKBP12, which is 108 amino acids in length (12 kDa) contains only an FK domain [11,12]. Other FKBPs, with large molecular weights, possess up to four consecutive FK binding domains (e.g., FKBP63/FKBP9, FKBP65/FKBP10). The FK domain, known as peptidyl-prolyl isomerase (PPIase) domain, binds to FK506 or rapamycin and causes immunosuppression. The enzymatic activity is inhibited by drug ligand binding [11,12]. FK domain also interacts with cellular proteins and modifies signaling pathways by its isomerase activity [13]. The PPIase activity accelerates the cis–trans isomerization of X-Pro peptide bond and is involved in protein folding. PPIase activity generates interconverting conformational polymorphism in protein partners, thereby modulating the function of protein partners [14]. These chaperone-related functions are common to all members of the FKBP family that contain an active PPIase/FK domain. At present, at least 16 FKBPs homologous proteins of varying molecular masses, ranging from 12 to 133 kDa, have been characterized in human tissues and classified on the basis of their molecular weight [11,12]. It is worth noting that, besides cyclophilins and FKBPs, also the parvulin-like Pin1 has PPIase activity [15]. Pin1 PPIase activity induces conformational changes of proteins involved in phosphorylation/dephosphorylation networks, including Ras-controlled pathway [15]. For this reason, it plays a role in malignant transformation and cancer [15]. Accordingly, Pin1 is overexpressed in a wide variety of human cancers, including breast, prostate, lung, ovary, cervical and brain tumors [15]. Along

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Please cite this article as: S. Romano, et al., Pleiotropic roles in cancer biology for multifaceted proteins FKBPs, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbagen.2015.01.004

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with FK domain, some FKBP family members (FKBP36/FKBP6, FKBP37/ AIP, FKBP38/FKBP8, FKBP51/FKBP5, FKBP52/FKBP4) contain Tetratricopeptide Repeat (TPR) motifs which mediate protein–protein interactions. The domain organization for several TPR cochaperones allows them to take part to receptor complexes by exerting activities which can vary depending on the particular TPR cochaperone [16]. TPR cochaperones compete for a common binding site in the C-terminal region of Hsp90 that includes the highly conserved -MEEVD sequence [16]. Although the TPR domains for each of these cochaperones are structurally similar and interact in a similar manner with Hsp90, the client protein bound by Hsp90 can influence the rank order of cochaperone recruitment to Hsp90–client complexes [17]. Additional functional motifs of FKBPs include Ef-Hand (EfH) calcium-binding domains [18]. The EF-hand motif contains a helix–loop–helix topology in which the Ca2 + ions are coordinated within the loop. FKBP22, FKBP23, FKBP60 and FKBP65 contain EF-hand motifs. Moreover, FKBP25, FKBP133 have nucleic acid binding regions, which allow them to localize into the nucleus [19]. Nuclear FKBP25 associates with HDACs [20], it promotes YY1 (Yin Yang 1) DNA binding [21] and p53 activity by enhancing MDM2 autoubiquitination and degradation [22]. Other FKBPs, although lacking nuclear localization signals, participate to transcriptional complexes and act as co transcription factors (FKBP12/FKBP1A [23], FKBP38/FKBP8 [23], FKBP51/FKBP5 [24,25], FKBP52/FKBP4) [26,27]. Finally, some FKBPs have endoplasmic reticulum (ER) signal sequences (FKBP22/FKBP19/FKBP11, FKBP24/FKBP22/ FKBP14, FKBP63/FKBP9, FKBP65/FKBP10) [11,12]. The enzymatic function of FKBPs in the endoplasmic reticulum is important for collagen biosynthesis [28]. Collagens contain a large number of proline residues that are post-translationally modified by these enzymes. Defects in ER-FKBPs can lead to diseases due to uncorrect collagen formation (e.g., Osteogenesis imperfecta, Ehlers-Danlos syndrome) [28–31]. FKBPs are highly conserved across the species, abundantly expressed in virtually all organisms and subcellular compartments and exert defined cellular roles, even in the absence of ligands. Recent studies [32] identified some members of FKBPs as active players in cancers, precancerous conditions and benign neoplasms, raising interest in this class of proteins as possible novel tumor targets and cancer biomarkers. Other family members appear to be protective against cancer. Aim of the present article is to review the current knowledge that involve 11 FKBP members in tumorigenesis and cancer.

[36]. It is conceivable that EGFR mutant is resistant to FKBP12 inhibition, but this remains to be investigated. In chronic lymphocytic leukemia (CLL), FKBP12 appeared to mediate CLL cells escape from the homeostatic control of TGF-β [37]. FK506 reactivated the TGF-β signal in CLL, and induced apoptosis by a mitochondria-dependent pathway in 33 out of 62 patient samples. FKBP12 acts as a natural ligand for the TGF-β type I receptor (TβR-I) [38] binding to a glycine- and serine-rich motif of TβR-I, capping its phosphorylation and stabilizing the inactive conformation of TβR-I. The PPIase core domain of FKBP12 is important for the interaction of the immunophilin with TβR-I. FK506 inhibits this interaction and promotes receptor transautophosphorylation [38], which in turn resulted in apoptosis of lymphocytes (both normal and leukemic). Increased levels of FKBP12 accounted for resistance to TGF-β in some cases. More frequently, expression of TβR-I was reduced in CLL [39], suggesting that, in a condition of a low receptor level, even normal levels of FKBP12 may be inhibitory and provoke resistance to the cytokine. 2.2. FKBP24 (gene FKBP14)

2. FKBP function in cancer

FKBP24/FKBP22/FKBP14, MW 24.17 KDa (Chromosome 7, 55033/ NC_000007.14 [Gene ID], NM_017946.3 [mRNA], NP_060416.1 [protein]). This is a PPIase which accelerates the folding of proteins during protein synthesis in endoplasmic reticulum lumen. FKBP24 is a rough endoplasmic reticulum resident protein essential for collagen biosynthesis [28]. Defects in FKBP24 are the cause of a variant EhlersDanlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss [40]. Defective FKBP24 leads to enlarged ER cisterns in dermal fibroblasts in vivo and an altered assembly of the extracellular matrix that might cause the generalized connective tissue involvement, typical of this disorder [40]. Halatsch et al. [41] identified FKBP24 among the molecules downstream to epidermal growth factor receptor (EGFR) signaling pathway, in glioblastoma multiform and emphasized the role of FKBP24 as molecular determinant responsible for resistance of glioblastoma to Erlotinib, a small molecule inhibitor of EGFR tyrosine kinase activity. The authors used a human glioblastoma cell model with three different phenotypes of response to Erlotinib and found five genes within the EGFR signaling pathway that modulated glioblastoma response to Erlotinib. Besides FKBP24, the authors found that another factor of resistance was a Rho family of GTPases called RAC1. Differently MYC, STAT1 and PTGER4, which is one of four receptors for Prostaglandin E2, were associated to Erlotinib sensitivity [41].

2.1. FKBP12 (gene FKBP1A)

2.3. FKBP25 (gene FKBP3)

FKBP12/FKBP1A, MW 11.95 KDa (Chromosome 20, 2280/ NC_000020.11 [Gene ID], NM_000801 [mRNA], NP_000792 [protein]), is the prototype FKBP [33], containing only a single FK (PPIase) domain. Khatua et al. found increased FKBP12 expression in childhood astrocytoma [34]. Among multiple FKBPs that were highly expressed in astrocytoma cells, FKBP12 appeared to have a pathogenetic role in tumor aggressiveness. The expression profiles of 13 childhood astrocytomas showed that FKBP12 overexpression was associated with increased expression of hypoxia-inducible transcription factor (HIF)-2α and epidermal growth factor receptor (EGFR) in malignant high-grade astrocytomas. The authors observed that the upregulated phenotype FKBP12/HIF2/EGFR was involved in angiogenesis of childhood highgrade astrocytomas, suggesting these genes represented a potential new therapeutic target. The FKBP12 tumor promoting effect on EGFR signaling in glial tumors was not consistent with a study by Mathea et al. [35], finding that FKBP12 acts as an endogenous inhibitor of EGFR phosphorylation and function. Notably, EGFR is often mutated in glial tumors with EGFR amplification. Particularly, mutant EGFRvIII, also known as EGFR type III, is very frequent. This mutant is highly oncogenic, signals constitutively and seems to generate a distinct set of downstream signals that may contribute to an increased tumorigenicity

FKBP25/FKBP3, MW 25.17 KDa (Chromosome 14, 2287/NC_000014.9 [Gene ID], NM_002013.3 [mRNA], NP_002004.1 [protein]), has a nuclear localization [42]. Sequence comparison suggested that the HD2-type histone deacetylases (HDAC) and the FKBP25 may have evolved from a common ancestor enzyme [42]. FKBP25 physically associates with the histone deacetylases HDAC1 and HDAC2, and with the HDACbinding transcriptional regulator Yin-Yang (YY)1. A FKBP25 immunoprecipitated complex contained deacetylase activity, and this activity was associated with the N-terminus of FKBP25, distinct from the FK506/rapamycin-binding domain [42,43]. FKBP25 also interacts with other chromatin-related proteins such as casein kinase II, Nucleolin and high-mobility group II protein [44]. Casein kinase II phosphorylation of several cytosolic and nuclear substrates, including Nucleolin, appears to be important for the regulation of cell growth. The interaction of FKBP25 with casein kinase II is thought to regulate cell growth, by promoting ribosome biogenesis and cell replication [44]. FKBP25 is a transcriptional target of MUM1 (Multiple Myeloma Oncogene 1)/ IRF4 (Interferon Regulatory Factor 4). This transcription factor is activated as a result of t(6;14)(p25;q32) in multiple myeloma, a neoplasia of plasmacells that benefits from histone deacetylase inhibitors treatment [45]. Increased MUM1 expression is seen in various B-cell

Please cite this article as: S. Romano, et al., Pleiotropic roles in cancer biology for multifaceted proteins FKBPs, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbagen.2015.01.004

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lymphomas and predicts an unfavorable outcome in some lymphoma subtypes [46]. A regulatory loop involving the tumor suppressor gene p53 and FKBP25 has been reported. FKBP25 stimulated auto-ubiquitylation and proteasomal degradation of mouse double minute 2 homolog (MDM2), leading to the induction of p53 and its downstream effector p21 [47]. Conversely, FKBP25 resulted decreased by p53 activation, as suggested by the finding of a reduced FKBP25 level in both human and murine immortalized and transformed cell lines, following induction of wildtype p53 by several DNA damaging stimuli [48]. Whether and how p53/FKBP25 might operate in cancer remain to be investigated.

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adenosine monophosphate (cAMP) signaling, due to defective G proteins α, that normally inhibit cAMP synthesis. Increases in intracellular cAMP concentrations determine impairments in signaling cascades associated with cell development and promote inflammation. Another important AIP interactor is the tyrosine kinase transmembrane receptor RET [58]. RET transduces a positive signal leading to survival, differentiation, or migration in the presence of its ligand glial cell line-derived neurotrophic factor, whereas, in the absence of ligand, a proapoptotic fragment is generated. The interaction between RET and AIP plays a role in transducing the RET-mediated proapoptotic signal, also mediated by preventing AIP binding to the antiapoptotic protein Survivin [58].

2.4. FKBP36 (gene FKBP6) 2.6. FKBP38 (gene FKBP8) FKBP36/FKBP6, MW 37.21 KDa (Chromosome 7, NC_000007.14 [Gene ID], NM_003602.4 [mRNA], NP_003593.3 [protein]). Genome-wide methylation profiling revealed FKBP6 promoter frequently methylated in cervical neoplasia, associated with HPV status and ethnicity in a Chilean population [49]. FKBP36 plays roles in germline development. It forms complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons to repress transposable elements and prevent their mobilization, which is essential for the germline integrity [50]. FKBP36 interacts with HSP90, HSP72, Clathrin Heavy Chain 1 and with GAPDH. Interestingly, GAPDH catalytic activity is inhibited by FKBP36 interaction. 2.5. FKBP37 (gene AIP) FKBP37/XAP3/AIP, MW 37.63 KDa (Chromosome 11, NC_000011.10 [Gene ID], NM_003977.2 [mRNA], NP_003968.2 [protein]). The aryl hydrocarbon receptor (AHR) interacting protein AIP is also known as ARA9 and XAP2 [51]. This protein displays structural similarity to FKBP52 but has distinct cellular roles and biochemical properties. Hsp90 was identified as physiological interaction partner of AIP, with binding contacts not only at the TPR domain but uncommonly also at the PPIase domain [51]. AHR is a member of the family of basic helix–loop–helix transcription factors, which binds several synthetic (halogenated aromatic hydrocarbons, dioxin-like compounds) or natural (derivatives of tryptophan, bilirubin, lipoxin A4 and prostaglandin G, dietary carotenoids) ligands [52]. Non-ligand bound AHR is retained in the cytoplasm as an inactive protein complex consisting of a dimer of Hsp90, Prostaglandin E Synthase 3 (p23) and a single molecule of AIP [52]. The dimer of Hsp90, along with p23, has a multifunctional role in the protection of the receptor from proteolysis, constraining the receptor in a conformation receptive to ligand binding [52]. AIP, in complex with Hsp90, binds to the AHR nuclear localization sequence, preventing the inappropriate trafficking of the receptor into the nucleus [52]. AIP affects the potency and efficacy of AHR agonists and regulates AHR signal transduction and is especially involved in the regulation of xenobiotic-metabolizing enzymes such as cytochrome P450 [51,52]. Additionally, AIP specifically binds to Hepatitis B Virus X-protein, a factor important for transactivation of viral and cellular genes [53]. Overexpression of AIP enhanced X transactivation activity, through involvement of the cellular protein kinase C pathway [54]. In pituitary adenoma, AIP gene functions as a tumor-suppressor gene [55]. Human pituitary adenomas are the most common intracranial neoplasms. Approximately 5% of them are familial adenomas. Germline AIP mutations have been shown to associate with the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur [56]. Around 75% of AIP mutations completely disrupt the C-terminal TPR domain, leading to failure of client–protein interaction, such a mechanism appeared to be sufficient to predispose to pituitary adenoma [57]. According to Tuominen et al. [56], mutated AIP causes a dysfunction in cyclic

FKBP38/FKBP8, MW 44.56 KDa (Chromosome 19, 23770/ NC_000019.10 [Gene ID], NM_012181.3 [mRNA], NP_001272500.1 [protein]). FKBP38 is a constitutively inactive PPiase which becomes active when binds to calmodulin and calcium [59]. FKBP38 forms heterodimer with calmodulin. Heterodimeric Ca2+/calmodulin/FKBP38 complex creates an enzymatically active protein, displaying an affinity for Bcl‐2. Association between Bcl‐2 and the activated PPIase site of Ca2+/calmodulin/FKBP38 complex promotes neuronal apoptosis [60]. Depletion of FKBP38 promotes neuronal cell survival [60]. Different results were obtained by Shirane and Nakayama [61] using another cancer cell system, namely HeLa cells. The authors found that FKBP38 exerted an anti apoptotic effect on such epithelial carcinoma cell line, due to anchoring Bcl-2 and Bcl-xL to mitochondria, where these proteins protected against Bax-mediated mitochondrial transition pore formation. The authors found that overexpression of FKBP38 prevented HeLa apoptosis. Consistently, functional inhibition of FKBP38 by a dominantnegative mutant or RNA interference promoted apoptosis [61]. The anti-apoptotic role of FKBP38 is in accordance with the role for this protein FKBP38 in the process of carcinogenesis of Schwannoma, a tumor of the nerve sheath [62]. Wang et al. [63] found an interaction between the Hepatitis C virus (HCV) non-structural protein NS5A and FKBP38. According to the authors, such an interaction played an important role in apoptosis evasion of HCV-infected liver cells. The interaction was mapped to the amino acids 148–236 of NS5A containing a Bcl-2 homology domain. NS5A is essential to viral replication and acts in concert with inflammation to promote evolution of hepatitis to liver cirrhosis and hepatocellular carcinoma [63]. NS5A-stably expressing Huh7 hepatoma cells were resistant to apoptosis and such resistance was specifically abrogated by depletion of FKBP38, using RNA interference [63]. Choi et al. found that FKBP38 interacted with the phosphatase of regenerating liver-3 (PRL-3) via N-terminal region, and promoted its degradation via protein–proteasome pathway [64]. Furthermore, FKBP38 suppressed PRL-3-mediated p53 activity and cell proliferation. PRL-3 is a member of protein tyrosine phosphatases implicated in tumorigenesis and metastasis of colorectal cancer [65] and melanoma [66]. These findings support a role for FKBP38 as a tumor suppressor, at least in cancers in which PRL-3 has pathogenetic role [64]. 2.7. FKBP51 (gene FKBP5) FKBP51/FKBP54/FKBP5, MW 51.21 KDa (Chromosome 6, 2289/ NC_000006.12 [Gene ID], NM_004117.3 [mRNA], NP_001139247.1 [protein]). A relevant role for FKBP51 in sustaining cancer cell growth and aggressiveness has been documented in a number of human cancers [67]. In particular, for glioma [68], prostate cancer [69] and melanoma [24] a strict correlation between aggressiveness and protein abundance has been demonstrated. Immunohistochemistry studies of tumoral samples are also consistent with increased FKBP51 expression in certain human cancers [70,71]. In physiological conditions, FKBP51 has a specialized role in mesenchymal stem cells [72]. In association with the

Please cite this article as: S. Romano, et al., Pleiotropic roles in cancer biology for multifaceted proteins FKBPs, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbagen.2015.01.004

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Zinc Finger protein ZNF 145, FKBP51 is preferentially expressed during the mitotically active phase preceding differentiation into the three mesodermal lineages, namely, osteogenesis, chondrogenesis, and adipogenesis [72]. A study on myeloproliferative disorders, showing that overexpression of FKBP51 regulates the growth factor independence of megakaryocyte progenitors, support the concept that FKBP51 is an essential factor for cell proliferation [73]. Evidence for a proliferative effect of FKBP51 have also been provided for glioma [68], prostate cancer [69], and melanoma [24]. FKBP51 determines androgen responsiveness in prostate cancer cells. Overexpression of FKBP51 contributes to prostate carcinogenesis through increased androgen signaling and cell proliferation [74]. Febbo et al. found that FKBP51 is regulated by androgens and physically associates with the androgen receptor before ligand binding in the androgen-dependent prostate cancer cell line LNCaP and prostate tumor tissue [75]. According to Makkonen et al. androgen receptor induces FKBP51 more rapidly and more strongly than does PSA, the classical androgen receptor target in prostate [76]. Periyasamy et al. found FKBP51 upregulated in association with cyclophilin Cyp40 in prostate cancer [69]. In androgen-dependent tumor cell lines, FKBP51 overexpression increased androgen receptor transcriptional activity in the presence and absence of androgens, while knockdown of FKBP51 dramatically decreased androgen-dependent gene transcription and proliferation [69]. FK506 showed similar inhibitory effects on androgeninduced growth of prostate cancer cells [69]. A study employing xenograph animal models showed that androgen-independent tumors, which arose from androgen-dependent tumsors, had levels of FKBP51 higher than androgen-dependent tumors. These findings suggested that continued activation of androgen receptor, despite androgen deprivation, may be sustained, at least partly, by the continued FKBP51 expression in some prostate cancers following castration [77]. Staibano et al. [70] found that immunochemical signal for FKBP51 in prostate tumors with high Gleason grade was increased compared with the signal of the well-differentiated tumors. The intracellular localization of the protein resulted in both cytoplasmic and nuclear signal, with a prevalent nuclear shifting in more aggressive tumors [70]. FKBP51 has documented anti-apoptosis effects in leukemia [78], melanoma [79], glioma [68], prostate cancer [69], retinal tumors [80]. A well characterized anti-apoptosis effect is mediated by NF-κB transcription factors. FKBP51 was found to be essential for chemotherapy [78,81] and radiotherapy [79] induction of these transcription factors, which in turn promoted transcription of anti-apoptotic proteins and induction of autophagy [79]. Gallo et al. [82] found that FKBP51 protects cells against oxidative stress and is a major mitochondrial factor that undergoes nuclear-mitochondrial shuttling during the stress response and exerts antiapoptotic mechanisms. FKBP51 positively regulates melanoma stemness and metastatic potential [24]. Particularly, an interaction between p300 and FKBP51 suggested the immunophilin participated to chromatin remodeling events. Experiments of chromatin immunoprecipitation showed that FKBP51 was bound to ABCG2 promoter, suggesting a role as cotranscription factor [24]. Additionally, FKBP51 increased the tumor promoter potential of the TGF-β [25]. Consistently, FKBP51 was found in p300/Smad 2/3 complexes. FKBP51 regulated expression of prooncogenic factors under TGF-β transcriptional control, namely SPARC, Vimentin and SLUG [25]. Levels of these factors decreased after FKBP51 knockdown. A study by Bhushan et al. [83] found increased FKBP5 expression in EphB6-silenced breast cancer cells, characterized by an aggressive behavior. Results from an array-based study, that were confirmed by quantitative PCR, identified FKBP5 among several genes involved in tumorigenesis and invasion, as important targets of a subset of significantly altered miRNAs, in EphB6 knocked down breast cancer cells [83]. Wang [84] suggested a role for FKBP51 as a tumor suppressor in pancreatic cancer, because FKBP51 acted as a scaffold for the phosphatase PHLPP, facilitating Akt dephosphorylation in vitro, and favoring

apoptotic response to gemcitabine. Fabian et al. [85] confirmed FKBP51 binds to Akt directly, but they found an interaction also via Hsp90. However, they observed an increase—not a reduction—in Akt S473 phosphorylation upon co-expression of FKBP51. The underlying reasons for the discrepancy in these results remain to be established. Fabian et al. found that FKBP51 inhibitors did not affect Akt S473 phosphorylation or targets downstream to Akt [85]. 2.8. FKBP52 (gene FKBP4) FKBP52/FKBP59/FKBP4, MW 51.80 KDa (Chromosome 12, 2288/ NC_000012.12 [Gene ID], NM_002014.3 [mRNA], NP_034349.1 [protein]). FKBP52 is a component of steroid receptors heterocomplexes, through interaction with HSP90 and HSP70 [86]. In the steroid receptor, the FKBP52-containing superchaperone complexes facilitate dimerization and nuclear transport of the receptor. FKBP52 was found ubiquitously expressed in breast cancer cell lines together with Cyp40, with differences in the pattern of expression [87]. FKBP52 protein levels were an order of magnitude greater than those for CyP40. FKBP52 mRNA expression correlated strongly with protein expression and was significantly higher in ER alpha-positive compared with ER alpha-negative cell lines [87]. Data generated by a study of mammosphere proteomics, and validated by Western blot, showed that FKBP52 was among the seven proteins overexpressed in breast cancer stem cells [88]. Interestingly, the differentially expressed proteins also included those involved in cell metabolisms such as GAPDH and fatty acid synthase, stress response proteins, including Hsp27. The authors found these proteins related to breast cancer tumorigenesis, cancer progression and resistance to current chemotherapies. Another proteomic study by Yang et al. [89] suggested that FKBP52 and S100A9 are biomarkers predictive of breast cancer response to doxorubicin [89]. A study by Solassol et al. [90], employing 60 early-stage primary breast cancers, 82 in situ breast carcinomas and 93 healthy controls, also found that FKBP52 was overexpressed in early-stage breast tissues, such as ductal in situ breast tumors, at the mRNA and protein levels. The authors also found FKBP52 auto-antibodies associated with early stage breast cancer and hypothesized that FKBP52 immunogenicity could be attributed to the increased protein expression [90]. A protein expression profile study in the livers of tumor-prone transgenic mouse models of hepatocellular carcinoma (HCC) identified FKBP52, together with Ferritin heavy chain, as proteins differentially expressed at the dysplastic stage [91]. Their levels in serum samples appeared to be increased in HCC, compared with control cases. Immunohistochemical analysis on tissue microarrays confirmed the differential expression of FKBP52 between HCC and the paired controls. The regulation of FKBP52 was also found to be relevant to HCC staging, with a dramatic decline at stage III. The study points to FKBP52 as biomarker for early HCC diagnosis [91]. 2.9. FKBP65 (gene FKBP10) ER FKBP65/FKBP10, MW 64.24 KDa (Chromosome 17, 60681/ NC_000017.11 [Gene ID], NM_021939.3 [mRNA], NP_068758.3 [protein]). FKBP65 is an endoplasmic reticulum-localized protein that associates with tropoelastin in the secretory pathway. FKBP65 is developmentally regulated and may be intimately involved in organogenesis [92]. Mutations in the gene encoding the rough endoplasmic reticulum protein FKBP65 cause autosomal-recessive osteogenesis imperfecta [29,30]. Expression of FKBP65 is decreased in epithelial ovarian cancer cells compared to benign tumor cells and to ovarian epithelium [93]. According to Quinn et al. [94], reduced FKBP65 protein is linked to the frequent loss of chromosome 17 in epithelial ovarian carcinomas, particularly high-grade serous carcinomas, as a consequence of the disruption of p53, at 17p13.1, and other chromosome 17 genes, which included FKBP10, at 17q21.1; and collagen I α 1, at 17q21.33. By

Please cite this article as: S. Romano, et al., Pleiotropic roles in cancer biology for multifaceted proteins FKBPs, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbagen.2015.01.004

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contrast, in prostate cancer [95], FKBP65 was overexpressed in tumors harboring rearrangements of a member of the ETS (E26 transformationspecific) transcription factor family, namely ETV1. ETS factors have been often found to be associated with cancer, because of gene fusion. In prostate cancer, the authors propose that FKBP65 can serve as diagnostic markers for molecular cancer subtypes harboring the ETV1 fusion gene rearrangements. Olesen et al. [96] identified FKBP65 as a novel marker associated with colorectal cancer. Analysis of 31 colorectal adenocarcinomas and 14 normal colorectal mucosa by quantitative PCR for FKBP10 showed a significant up-regulation in tumors, when compared with normal mucosa. Immunohistochemical analysis of 26 adenocarcinomas and matching normal mucosae showed that FKBP65 was not present in normal colorectal epithelial cells, but it was strongly expressed in colorectal cancer cells. 2.10. FKBP133 (gene FKBP15) FKBP133/KIAA0674/FKBP15, MW 133.63 (Chromosome 9, 23307/ NC_000009.12 [Gene ID], NM_015258.1 [mRNA], NP_056073.1 [protein]). This is a protein with homologies to Wiskott Aldrich syndrome protein WASP. FKBP133 is involved in the transport of early endosomes from the cell periphery to the perinuclear region, by interacting with actin filaments and microtubules, besides endosomes [97]. FKBP133 was shown to function as part of the clathrin-coated vesicle-mediated endocytosis machinery. Through a differential gene expression screen using subtractive suppression hybridization, it has recently been found that FKBP133 is a marker of ulcerative colitis, an inflammatory disease of the colonic mucosa and a precancerous condition [98]. Upregulation of FKBP133 in activated monocytes undergoing differentiation into macrophages, which are active in endocytosis, is suggested to play a role in gut inflammation. 2.11. FKBPL (gene FKBPL) FKBPL/DIR1/Wisp1/FKBPL, MW 42.00 KDa (Chromosome 6, 63943/ NC_000006.12 [Gene ID], NM_022110.3 [mRNA], NP_071393.2 [protein]). FK506-binding protein like FKBPL) is a divergent member of

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this family [99]. It shares homology with the FKBP family (in particular FKBP52/51 and cyclophilin 40) in mostly in the C-terminal TPR domain, but lacks the PPIase domain that is required for enzymatic activity. Interestingly, this noncanonical member has shown several antitumor activities, carried out by several diverse mechanisms. Following high-dose radiation stress, FKBPL binds to newly synthesized p21, in a complex with Hsp90, increasing p21 stability by preventing its proteasomal degradation and promotes the G2 arrest. FKBPL knockdown, and presumably reduced p21, confers resistance to radiation. According to Bublik et al. [100], the association of the FKBPL/Hsp90/p21 complex with high levels of G2 and S phase expressed protein 1 (GTSE-1) increased p21 stabilization and caused resistance to taxanes chemotherapy [100]. The N-terminal region of FKBPL protein is responsible for the antiangiogenic activity, the sequence is unique, with no homology to other FKBPs or other proteins. The antiangiogenic mechanism is dependent on interaction of secreted FKBPL with CD44 [101]. FKBPL interacts with estrogen receptor alpha. Breast cancer cells stably overexpressing FKBPL become highly sensitive to the anti-estrogens tamoxifen and fulvestrant, whereas FKBPL knockdown reversed this phenotype. FKBPL expression was correlated with increased overall survival and distant metastasis-free survival in breast cancer patients. FKBPL by increasing breast cancer sensitivity to endocrine therapies is thought to improve outcomes of this tumor [102]. 3. Conclusions The FKBPs represent a unique protein family encompassing several multi-domain proteins. The biological roles of the human FKBPs appear to be diverse and frequently involve the regions flanking the PPIase domain. Although residues crucial for PPIase activity are conserved in FKBPs, residues of the proline-rich loop above the PPIase pocket differ. These differences, together with the presence of diverse specialized domains account for the multiple and sometimes divergent partners and functions of the FKBPs. Their multifaceted activities are consistent with the wide variety of cancer-related processes in which a relevant role for FKBPs has been demonstrated (see Table 1), including apoptosis, cell proliferation, angiogenesis, stress response, protein trafficking,

Table 1 FKBPs involved in human neoplasias and cancer-related diseases.

FKBP12/FKBP1A FKBP24/FKBP2/FKBP14 FKBP25/FKBP3 FKBP36/FKBP6 FKBP37/ARA9/XAP2/AIP FKBP38/FKBPR8/FKBP8

FKBP51/FKBP54/FKBP5

FKBP52/FKBP59/FKBP4 FKBP65/FKBP10

FKBP133/WAFL/FKBP15 FKBPL/DIR1/ Wisp1/FKBPL

Mechanism

Tumor

Apoptosis resistance Angiogenesis Resistance to EGFR inhibitor erlotinib Epigenetic modifier Epigenetic modifier Regulation of aryl hydrocarbons receptor signal Apoptosis evasion Negative regulation of the tumor promoter PRL-3 Apoptosis resistance, cell proliferation, invasion and metastatis, androgen receptor signaling Apoptosis sensitation Steroid receptor signaling, cell proliferation Control of folding, trafficking and secretion of extracellular matrix proteins Endocytosis clathryndependent. Inflammation Increase in tamoxifen response. anti angiogenesis

Precancerous/benign neoplasm

T. Promoter

References

CLL Childhood astrocytoma Glioblastoma multiform

+ + +

[37] [34] [41]

Plasmocytoma, B-cell lymphomas Cervical cancer HPV+ (loss)

+

[44–46]

Pituitary adenomas Hepatocarcinoma Melanoma, colorectal cancer

Schwannoma, hepatitis C

Leukemia, Melanoma, glioma, prostate cancer, breast cancer

Idiopathic myelofibrosis

T. Suppressor

+ + +

[62,63] [64–66]

+

[24,25,67–71,73–81,83]

+

Pancreatic cancer Breast cancer Early hepatocellular carcinoma Ovarian cancer Prostate cancer Colorectal cancer

+ + + + + + +

Ulcerative colitis Breast cancer

[49] [54–58]

+

[84] [87–90] [91] [93,94] [95] [96] [97,98] [99,101,102]

Please cite this article as: S. Romano, et al., Pleiotropic roles in cancer biology for multifaceted proteins FKBPs, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbagen.2015.01.004

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Please cite this article as: S. Romano, et al., Pleiotropic roles in cancer biology for multifaceted proteins FKBPs, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbagen.2015.01.004