Cancer genetics and genomics of human FOX family genes

Cancer genetics and genomics of human FOX family genes

Cancer Letters xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Cancer Letters journal homepage:

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Cancer Letters xxx (2012) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Cancer Letters journal homepage:


Cancer genetics and genomics of human FOX family genes Masuko Katoh a, Maki Igarashi b, Hirokazu Fukuda b, Hitoshi Nakagama b,c, Masaru Katoh c,⇑ a

M & M Medical BioInformatics, Tokyo 113-0033, Japan Division of Cancer Development System, National Cancer Center, Tokyo 104-0045, Japan c Division of Integrative Omics and Bioinformatics, National Cancer Center, Tokyo 104-0045, Japan b

a r t i c l e

i n f o

Article history: Received 25 July 2012 Received in revised form 20 September 2012 Accepted 21 September 2012 Available online xxxx Keywords: FOX Pioneer factor Nuclear hormone receptor Germ-line variation Somatic mutation

a b s t r a c t Forkhead-box (FOX) family proteins, involved in cell growth and differentiation as well as embryogenesis and longevity, are DNA-binding proteins regulating transcription and DNA repair. The focus of this review is on the mechanisms of FOX-related human carcinogenesis. FOXA1 is overexpressed as a result of gene amplification in lung cancer, esophageal cancer, ER-positive breast cancer and anaplastic thyroid cancer and is point-mutated in prostate cancer. FOXA1 overexpression in breast cancer and prostate cancer is associated with good or poor prognosis, respectively. Single nucleotide polymorphism (SNP) within the 50 -UTR of the FOXE1 (TTF2) gene is associated with thyroid cancer risk. FOXF1 overexpression in breast cancer is associated with epithelial-to-mesenchymal transition (EMT). FOXM1 is overexpressed owing to gene amplification in basal-type breast cancer and diffuse large B-cell lymphoma (DLBCL), and it is transcriptionally upregulated owing to Hedgehog-GLI, hypoxia-HIF1a or YAP-TEAD signaling activation. FOXM1 overexpression leads to malignant phenotypes by directly upregulating CCNB1, AURKB, MYC and SKP2 and indirectly upregulating ZEB1 and ZEB2 via miR-200b downregulation. Tumor suppressor functions of FOXO transcription factors are lost in cancer cells as a result of chromosomal translocation, deletion, miRNA-mediated repression, AKT-mediated cytoplasmic sequestration or ubiquitination-mediated proteasomal degradation. FOXP1 is upregulated as a result of gene fusion or amplification in DLBCL and MALT lymphoma and also repression of miRNAs, such as miR-1, miR-34a and miR-504. FOXP1 overexpression is associated with poor prognosis in DLBCL, gastric MALT lymphoma and hepatocellular carcinoma but with good prognosis in breast cancer. In neuroblastoma, the entire coding region of the FOXR1 (FOXN5) gene is fused to the MLL or the PAFAH1B gene owing to interstitial deletions. FOXR1 fusion genes function as oncogenes that repress transcription of FOXO target genes. Whole-genome sequencing data from tens of thousands of human cancers will uncover the mutational landscape of FOX family genes themselves as well as FOX-binding sites, which will be ultimately applied for cancer diagnostics, prognostics, and therapeutics. Ó 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Forkhead-box (FOX) proteins, regulating cell growth and differentiation as well as embryogenesis and longevity, have a conserved FOX domain and extra-FOX protein–protein interaction (PPI) domains or regions [1–5]. A FOX domain of approximately 100 amino acids in length was originally identified as the conserved region among mammalian FOXA1 (HNF-3a), FOXA2 (HNF-3b), FOXA3 (HNF-3c), and Drosophila Fork head [6,7]. The FOX domain is also known as Winged-helix domain because its three-dimensional structure consists of two wing-like loops and three a-helices [8,9]. The FOX domain is involved in DNA binding [10,11], while extra-FOX regions are involved in interaction with components ⇑ Corresponding author. Address: Division of Integrative Omics and Bioinformatics, National Cancer Center, 5-1-1 Tsukiji, Chuo Ward, Tokyo 104-0045, Japan. E-mail address: [email protected] (M. Katoh).

of transcriptional activators, transcriptional repressors, or DNA repair complexes [12–14]. FOX family members are DNA-binding proteins involved in transcriptional regulation as well as DNA repair. Congenital disorders or hereditary diseases caused by FOXC1, FOXC2, FOXE1, FOXE3, FOXL2, FOXN1, FOXP2, and FOXP3 genes have previously been reviewed [1,2]. Germ-line FOXP2 point mutations result in a speech and language disorder of the verbal dyspraxia type [15], whereas germ-line FOXP1 deletions occur in patients with learning disabilities, developmental delays, and speech and language disorders [16]. The FOXF1-MTHFSD-FOXC2-FOXL1 locus at human chromosome 16q24.1 is commonly deleted in neonatally lethal cases that have alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), and frameshift or nonsense mutations of FOXF1 were identified as the cause of ACD/MPV [17]. Single nucleotide polymorphisms (SNPs) in the FOXA2, FOXJ1, FOXO3, and FOXP1 genes are associated with a fasting glycemic

0304-3835/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: M. Katoh et al., Cancer genetics and genomics of human FOX family genes, Cancer Lett. (2012), j.canlet.2012.09.017


M. Katoh et al. / Cancer Letters xxx (2012) xxx–xxx

Table 1 Germ-line mutation or SNP of human FOX family genes associated with physiology or diseases. Gene

Chr. locus




20p11.21 19q13.32 15q22.2 9q21.2 6p25.3 16q24.1 5q12-q13 1p33 1p31.3 9p24.3 2q13 9p12 9q21.11 9q21.11 9q21.11 9q21.11 9q22.33


1p33 16q24.1 6p25.3 14q12 8q24.3 5q35.1 10q26.2 2p11.2 17q25.1 12p13.31 1p34.2 7p22.1 17q25.3 16q24.1 3q22.3 12p13.33 17q11.2 2p16.3 14q31.3q32.11 12q24.11 13q14.11


1p34.2 6q21


Xq13.1 3p13


7q31.1 Xp11.23


6p21.1 6p25.3 11q23.3 Xp11.21 20q11.21

Germ-line mutations or variations

Somatic mutations in human cancers

Fasting glycemic trait (SNP)

Amp (Lung, Esophageal, Breast, Thyroid) Mut (Prostate) Amp (Pancreas)

Axenfeld–Rieger syndrome Lymphedema–distichiasis syndrome

Amp (Breast)

Bamforth–Lazarus syndrome Thyroid cancer (SNP) Anterior segment mesenchymal dysgenesis Alveolar capillary dysplasia with misalignment of pulmonary veins

Del (Prostate)

Rett syndrome

Amp (Hepatoblastoma)

Allergic rhinitis (SNP)

Amp (Breast)

Blepharophimosis, ptosis, and epicanthus inversus syndrome

Mut (Granulosa-cell tumor of ovary) Amp (Breast, DLBCL, B-CLL, MPNST)

T-cell immunodeficiency, congenital alopecia, nail dystrophy

Type 2 diabetes (SNP)

Transloc (Alveolar rhabdomyosarcoma) Del (Prostate)

Premature ovarian failure Longevity (SNP)

Transloc (Secondary leukemia)

Learning disability, developmental delay, speech and language disorder Generalized vitiligo (SNP)

Speech and language disorder (verbal dyspraxia) Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked

Transloc (ALL) Amp (DLBCL, MALT) Transloc (DLBCL, MALT, B-ALL, Prostate) Del (Philadelphia-negative myeloproliferative neoplasm, Kidney) Mut & Del (Breast, Prostate)

Del-fuse (Neuroblastoma)

FOXC1, FOXF2 and FOXQ1 genes are clustered at human chromosome 6p25.3; FOXC2, FOXF1 and FOXL1 genes are clustered at 16q24.1; FOXD2 and FOXE3 genes are clustered at 1p33; FOXJ3 and FOXO2 (FOXO6) genes are clustered at 1p34.2; FOXD4L3, FOXD4L4, FOXD4L5 and FOXD4L6 genes are clustered at 9q21.11. SNP: single nucleotide polymorphism; Amp: gene amplification; Mut: point mutation; Transloc: translocation; Del: deletion; Del-fuse: interstitial deletion resulting in gene fusion; DLBCL: diffuse large B-cell lymphoma; B-CLL: B-cell chronic lymphocytic leukemia; MPNST: malignant peripheral nerve sheath tumor; ALL: acute lymphoblastic leukemia; MALT: mucosaassociated lymphoid tissue lymphoma.

trait, allergic rhinitis, longevity, and generalized vitiligo, respectively [18–21]. The haplotype of six SNPs in the FOXO1 gene is associated with a decreased risk of type 2 diabetes (T2DM) in the German population [22], whereas SNP rs2721068 in the FOXO1 gene is associated with an increased risk of T2DM in German and Finnish populations [23]. Because FOX family members are involved in a variety of processes during embryogenesis and adult

tissue homeostasis, germ-line mutations or variations of FOX family members are often associated with human congenital disorders and diseases (Table 1). Human cancers occur in a multi-step manner as a result of accumulation of epigenetic changes and genetic alterations [24–26]. Somatic mutations of FOX family genes in various types of human cancers have been reviewed previously [3–5,27–29]. Currently,

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M. Katoh et al. / Cancer Letters xxx (2012) xxx–xxx

novel data on somatic mutations of FOX family members are accumulating in the public database owing to the advancement and spread of the exome or whole-genome sequencing technologies. Point mutations, gene amplifications, and translocations of FOX family genes in tumor cells directly alter the functions of FOX family members, whereas aberrant activation of cancer-associated signaling cascades involved in transcriptional regulation leads to the dysregulated expression of FOX family members. Here, the genetic alterations and dysregulated expression of FOX family genes are reviewed, with a focus on the mechanisms of human carcinogenesis.

2. FOXA1 The FOXA1 gene at human chromosome 14q21.1 is amplified in lung cancer, esophageal cancer [30], estrogen receptor (ER)-positive breast cancer [31], anaplastic thyroid cancer [32], and metastatic prostate cancer [33]. In addition to gene amplifications, FOXA1 point mutations also occur in prostate cancer [34]. FOXA1 is overexpressed in some cases of lung cancer, esophageal cancer, breast cancer, and thyroid cancer as a result of gene amplification [30–32]. However, gene amplification of FOXA1 is relatively rare in primary breast cancers [35]. Because FOXA1 is a direct target gene of estrogen-ER signaling [36], FOXA1 is upregulated in most cases of ER-positive breast cancer as a result of ER-dependent transcriptional regulation [37]. FOXA1 is also preferentially upregulated in androgen-receptor (AR)-dependent prostate cancer [38]. FOXA1 is the representative member of the FOXA subfamily, consisting of an N-terminal transactivation domain, a central FOX domain, and a C-terminal histone-binding transactivation domain [39]. The FOX domain and the C-terminal domain of FOXA1 are involved in its association with double-strand genomic DNA and histone H3/H4, respectively. FOXA1 binds to the Forkhead-binding

Compact chromatin


Open chromatin



Cell lineage - or tumor type - specific transcription Fig. 1. The context-dependent transcriptional program of FOXA1. FOXA1 is a pioneer factor that opens up compact chromatin. Other transcription factors, such as estrogen receptor (ER), androgen receptor (AR) and glucocorticoid receptor (GR), subsequently bind to the FOXA1-dependent open chromatin regions, which activates cell lineage- or tumor type-specific transcriptional programs. FOXA1 overexpression is associated with good prognosis in breast cancer but with poor prognosis in prostate cancer.


motif within highly compacted chromatin regions and then induces the relaxation of FOXA1-bound loci through the replacement of linker histone H1, the dimethylation of histone H3 lysine 4 (H3K4me2), and the demethylation of genomic DNA [10,40–43]. FOXA1 with chromatin opening potential is a ‘‘pioneer factor’’ [44,45] that releases the safety catch for other transcription factors to trigger transcriptional programs (Fig. 1). FOXA1 and ER are required for transcription of TFF1, RPS6KL1, and ABCC5 in estrogen-dependent breast cancer cells [36]. FOXA1 and AR are required for transcription of PSA in androgendependent prostate cancer cells [46], while FOXA1 and MYBL2/ CREB1 are required for transcription of CCNE2 and E2F1 in castration-resistant prostate cancer cells [47]. FOXA1 point mutations result in repression of AR-dependent transcription and increased proliferation of prostate cancer cells [34]. FOXA1 upregulation is associated with good prognosis in breast cancer patients owing to its preferential upregulation in the ER-positive subtype [48], whereas FOXA1 upregulation is associated with poor prognosis in prostate cancer patients [49]. Upregulation or high expression levels of FOXA1 is associated with prognosis of cancer patients in a context-dependent manner that depends on the existence of FOXA1 cofactors involved in cell lineage- or tumor type-specific transcriptional programs and FOXA1 point mutations altering the transcriptional landscape.

3. FOXM1 The FOXM1 gene at human chromosome 12p13.33 is amplified in 5.6% of breast cancers [35], 42% of non-Hodgkin’s lymphomas [50], and 58% of malignant peripheral nerve sheath tumors [51]. Amplification of the FOXM1 gene is enriched in basal-type breast cancers, whereas amplification of FOXM1 gene is commonly observed in three major subtypes of non-Hodgkin’s lymphoma: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Bcell chronic lymphocytic leukemia (CLL). FOXM1 mRNA is upregulated in basal-type breast cancer [35], non-Hodgkin’s lymphoma [50], and malignant peripheral nerve sheath tumors [51] as a result of gene amplification of FOXM1 itself. Because Hedgehog signaling to GLI [52,53], hypoxia signaling to HIF-1a [54], and the YAP-TEAD transcriptional complex [55] are all involved in FOXM1 transcription, FOXM1 mRNA is also upregulated in basal cell carcinoma [52], pancreatic cancer [56], cervical cancer [57], head and neck squamous cell carcinoma (SCC) [58], lung cancer [59], hepatocellular carcinoma (HCC) [60], medulloblastoma [61], malignant mesothelioma [55], and bladder cancer [62]. FOXM1 protein, consisting of FOX domain and transactivation domain, is phosphorylated by ERK on Ser331 and Ser704 in the Pro-Gly-Ser-Pro (PGSP) motif. Unphosphorylated FOXM1 is located in the cytoplasm, whereas phosphorylated FOXM1 is located in the nucleus [63]. Aberrant activation of receptor tyrosine kinases (RTKs), RAS, RAF, or MAPK2 in tumor cells leads to ERK-mediated phosphorylation and nuclear accumulation of FOXM1, which promotes the FOXM1-dependent transcriptional program. FOXM1 is functionally activated in tumor cells as a result of transcriptional upregulation of FOXM1 mRNA as well as ERK-mediated phosphorylation of FOXM1 protein (Fig. 2). Overexpression of FOXM1 leads to direct upregulation of CDC25B, CCNB1 (Cyclin B1), AURKB (Aurora kinase B), PLK1 (Polo-like kinase 1), CENPA, CENPB, MYC (c-Myc), SKP2, MMP2, and VEGF [64–67] as well as indirect upregulation of ZEB1 and ZEB2 through microRNA-200b (miR-200b) downregulation [68]. The SKP2 gene encodes a component of the ubiquitin ligase involved in the proteasome-mediated degradation of CDKN1A (p21, CIP1, or WAF1), CDKN1B (p27, or KIP1), FOXO1, DUSP1, and SMAD4 [69].

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Growth factor



Patched RTK





α HIF1α






FOXM1 - target genes CDC25B, CCNB1, AURKB, PLK1, CENPA, CENPB, MYC, KP2, etc Malignant phenotypes

Fig. 2. FOXM1 upregulation results in malignant phenotypes. FOXM1 is transcriptionally upregulated by the Hedgehog-GLI, the hypoxia-HIF1a, and the YAP-TEAD signaling cascades. In addition, FOXM1 mRNA is overexpressed owing to gene amplification in basal-type breast cancer, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and B-cell chronic lymphocytic leukemia (CLL). The aberrant activation of receptor tyrosine kinase (RTK)-RAS-RAF signaling cascade leads to ERK-mediated FOXM1 phosphorylation, which results in transcriptional upregulation of FOXM1 target genes, such as CDC25B, CCNB1, AURKB, PLK1, CENPA, CENPB, MYC, and SKP2. Because FOXM1 induces malignant phenotypes, FOXM1 overexpression is associated with poor prognosis in lung cancer, medulloblastoma, breast cancer, gastric cancer, and pancreatic cancer.

Upregulation of CDC25B, cyclin B1, AURKB, PLK1, CENPA, CENPB and MYC and the downregulation of p27KIP1 and p21WAF1 are involved in cell-cycle progression. MMP2 and VEGF are involved in invasion and angiogenesis, respectively. ZEB1 and ZEB2 are involved in epithelial-to-mesenchymal transition (EMT). Because FOXM1 induces malignant phenotypes (Fig. 2), FOXM1 protein upregulation is associated with poor prognosis for various types of human cancers, including lung cancer, medulloblastoma, breast cancer, gastric cancer, and pancreatic cancer [59,61,66,70]. 4. FOXO subfamily genes The FOXO1, FOXO2 (FOXO6), FOXO3, and FOXO4 genes are FOXO subfamily members [3]. The RXRSCTWPL motif in the N-terminal region and the FOX domain containing a RRRAXSMD motif are conserved in all members of the FOXO subfamily, while the RXRXXSNASXXSXRLSP motif in the middle region is conserved in the FOXO1, FOXO3, and FOXO4 proteins. In the nucleus, FOXOs bind to their consensus DNA-binding motif to activate transcription of their target genes, such as CDKN1A, CDKN1B, GADD45, SOD2 (manganese superoxide dismutase), FASLG (Fas ligand), TRAIL, and BIM (BCL2-like 11) [12,71,29]. CDKN1A and CDKN1B are cyclin-dependent kinase inhibitors involved in cell cycle arrest at the G1 phase. GADD45 and SOD2 are involved in DNA repair and stress response, respectively. Fas ligand, TRAIL and BIM are involved in apoptosis. FOXO transcription factors can function as tumor suppressors. The FOXO1 gene at human chromosome 13q14.11 is fused to either the PAX3 or the PAX7 gene as a result of chromosomal translocation in alveolar rhabdomyosarcoma. The FOXO3 gene at 6q21

and the FOXO4 gene at Xq13.1 are fused to the MLL gene as a result of chromosomal translocation in secondary leukemia and acute lymphoblastic leukemia (ALL), respectively [29]. The FOXO1 gene is located within the commonly deleted region in prostate cancer, and the FOXO1 mRNA level is frequently downregulated in prostate cancer [72]. The FOXO1 gene is a direct target of the EWS-FLI1 fusion repressor, and FOXO1 mRNA is downregulated in Ewing’s sarcoma cells [73]. FOXO4 mRNA, one of the targets of miR-499-5p, is downregulated in some cases of colorectal cancer that have miR499-5p upregulation [74]. The FOXO proteins consist of FOX domain and transactivation domain. The function of FOXO proteins is regulated by posttranslational modifications, such as phosphorylation, acetylation, and ubiquitination [75,76]. AKT phosphorylates FOXO1, FOXO3, and FOXO4 on Ser/Thr residues in three RXRXXS/T motifs, and casein kinase 1 (CK1) subsequently phosphorylates the Ser residues in SXXS sequence neighboring the third RXRXXS/T motif. Priming phosphorylation by AKT combined with subsequent phosphorylation by CK1 leads to sequestration of FOXOs in the cytoplasm, which abrogates their transcriptional functions in the nucleus [77,78]. FOXO transcriptional activity is also inhibited owing to phosphorylation by IKKb, ERK1/2, DYRK1, CDK2, and NLK, as well as acetylation by CBP, p300, and PCAF [76,79]. Growth factors, such as insulin, IGF1, EGF, and FGF, bind to ligand-specific RTKs to activate the PI3K-AKT signaling cascade, whereas PTEN inhibits the PI3K-AKT signaling cascade. Aberrant PI3K-AKT signaling activation based on gain-of-function mutations of RTKs or PI3K components or loss-of-function mutations of PTEN leads to functional loss of FOXO transcription factors due to cytoplasmic sequestration.

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SKP2 is an E3 ubiquitin ligase for FOXO1 [69], while MDM2 is an E3 ubiquitin ligase for FOXO1, FOXO3, and FOXO4 [80,81]. Because poly-ubiquitinated FOXO proteins are degraded by the proteasome, SKP2 and MDM2 are involved in degradation of FOXO transcription factors. MDM2, which is induced by p53, is also involved in the degradation of p53 by the proteasome. Gene amplification and overexpression of MDM2 in breast cancer, glioblastoma, osteosarcoma, and liposarcoma [82] leads to functional loss of p53 and FOXO proteins due to proteasome degradation. The tumor suppressor functions of FOXO transcription factors are lost in cancer cells as a result of chromosomal translocations or deletions of FOXO genes, miRNA-mediated repression of FOXO mRNAs, AKT-mediated cytoplasmic sequestration of FOXO proteins, or ubiquitination-mediated proteasomal degradation of FOXO proteins. 5. FOXP1 The FOXP1 gene at human chromosome 3p13 is fused to the immunoglobulin heavy chain (IGH) locus as a result of chromosomal translocations in DLBCL and mucosa-associated lymphoid tissue (MALT) lymphoma [27,83]. FOXP1 is fused to either the PAX5 or the ABL1 gene in B-ALL [84,85], and is fused to the ETV1 gene in prostate cancer [86]. The FOXP1 gene is amplified in DLBCL and MALT lymphoma either with or without translocation [87]. By contrast, the FOXP1 gene is deleted in Philadelphia chromosomenegative myeloproliferative neoplasms [88] and clear cell-type kidney cancer [89]. FOXP1 mRNA is upregulated in MALT lymphoma with FOXP1 translocation [83], non-MALT gastric cancer [90], and oral SCC with repressed miR-504 [91]. FOXP1 protein is upregulated in DLBCL and MALT lymphoma with FOXP1 translocation [87] or repressed miR-34a [92] and is also upregulated in HCC with repressed miR1 [93]. FOXP1 mRNA is downregulated in kidney cancer [89], and colon cancer [90]. FOXP1 expression is induced by translocation, gene amplification, and estrogen-ER signaling and is repressed by miR-1, miR-34a, and miR-504. The FOXP1 transcription factor consists of a poly-Gln region, a C2H2-type zinc finger domain, a leucine zipper domain, and a FOX domain [90]. Rodent Foxp1 represses the transcription of Sox17 and Nkx2.5 in developing cardiomyocytes [94] and activates the transcription of Rag1 and Rag2 in developing B cells [95]. The ability of FOXP1 to repress or activate the transcription of target genes depends on either the cellular lineage or the binding partner. FOXP1 functions as a cancer driver in some tumors but as a tumor suppressor in others [96]. Wild-type FOXP1 acts like a tumor suppressor gene in many tissues or organs, while shorter isoforms of FOXP1 act like oncogenes in DLBCL and MALT [27]. In addition to cell lineage- or tumor type-specific transcriptional program, existence of shorter isoforms affects the behavior of FOXP1 during carcinogenesis. FOXP1 is therefore associated with the prognosis of cancer patients in a context-dependent manner. For example, the prognosis of FOXP1-positive DLBCL [97], gastric MALT lymphoma [98], and HCC [99] is poor, but the prognosis of FOXP1-positive breast cancer is good [100]. 6. FOXR1 FOXR1, also known as FOXN5, was initially identified and characterized as a cancer-associated gene located at human chromosome 11q23.3, which is frequently deleted in neuroblastoma [101]. In neuroblastoma, FOXR1 is fused to the MLL or the PAFAH1B gene owing to interstitial deletions which results in the overexpression of fusion transcripts containing the entire coding region of FOXR1 [102]. FOXR1 silencing in HOS osteosarcoma cells leads


to the upregulation of FOXO target genes, such as CDKN1A and CDKN1B, and the inhibition of cellular proliferation. The overexpression of FOXR1 in JoMa1 neuroblasts that have an inducible ER-MYC transgene promotes cellular proliferation even in the absence of MYC induction [102]. Taken together, these findings indicate that FOXR1 fusion genes function as oncogenes that repress the transcription of FOXO target genes. 7. Other FOX genes FOXC2 expression is regulated by a network of Hedgehog and TGFb signaling cascades [53,103]. Because FOXC2 is involved in EMT [103] and angiogenesis [104], FOXC2 expression is associated with the poor prognosis of basal-type breast cancers that co-express GLI1 [105] and esophageal SCC [106]. FOXE1 functions as a pioneer factor that opens up compact chromatin to promote thyroid hormone-induced transcriptional regulation [107]. The rs1867277 SNP within the 50 -UTR of the FOXE1 gene, which creates a binding site for USF1 and USF2, is associated with susceptibility to thyroid cancer [108]. FOXE1 is repressed in cutaneous SCC as a result of promoter hypermethylation [109] but is upregulated in basal cell carcinoma as a result of Hedgehog-GLI signaling activation [110]. The FOXF1 locus at human chromosome 16q24.1 is deleted in prostate cancer, and FOXF1 mRNA expression is downregulated in some cases of prostate cancer [111]. Copy number aberrations and expression levels of FOXC2 and FOXL1, which neighbor FOXF1, should be investigated to determine which FOX gene is truly involved in prostate cancer. Expression of FOXF1 mRNA is also downregulated in some cases of breast cancer and colorectal cancer [112,113]. FOXF1 downregulation in breast cancer cells is due to epigenetic silencing, and re-expression of FOXF1 using pharmacologic unmasking is associated with cell cycle arrest at the G1 phase [112]. Overexpression of FOXF1 is associated with a mesenchymal phenotype and an increased invasion potential in breast cancer [114]. FOXF1 upregulation leads to EMT manifested by mesenchymal phenotype and G1 arrest in breast cancer. FOXQ1 is upregulated by TGFb signaling and is also involved in EMT [115,116]. Because FOXQ1 is expressed in basal-type breast cancers with a higher grade, the prognosis of FOXQ1-positive breast cancer is poor [117]. Gene amplification of FOXA2 in pancreatic cancer [118], FOXD3 and FOXJ1 in breast cancer [35], and FOXG1 in hepatoblastoma [119] has been reported. Point mutations of FOXL2 in granulosacell ovary tumors [120] as well as point mutations and deletions of FOXP3 in breast and prostate cancer [121,122] have also been reported. 8. Conclusion FOX family genes are involved in carcinogenesis as oncogenes and/or tumor suppressor genes. Germ-line variation of FOXE1 leads to a genetic predisposition to thyroid cancer. Epigenetic changes of FOX family genes as well as genetic alterations of FOX family genes, such as copy number aberration, translocation and point mutation, occur in various types of human cancers (Table 1). Overexpression of FOXA1 or FOXP1 is associated with good or poor prognosis depending on the tumor type, whereas overexpression of FOXM1 is associated with poor prognosis. 9. Perspectives Foxa1 and Foxa2 are redundantly involved in progression of hepatocarcinogenesis through induction of the AR-target genes in male mice, whereas Foxa1 and Foxa2 are redundantly involved in

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Mutation landscape of FOX family genes and FOX-binding sites in human cancers

3rd - generation Sequencing (Pacific Biosciences) 2nd - generation Sequencing (454 Life Science, Illumina) 1st - generation Sequencing (Sanger)

Cancer diagnostics, prognostics & therapeutics

Fig. 3. Whole-genome sequencing in the era of personalized medicine.

suppression of hepatocarcinogenesis through induction of the ERtarget genes in female mice [123]. In addition, point mutations or SNPs at the FOXA2-binding sites within the regulatory regions of PPM1L, FGL1, BTG1, and ABCC4 genes preferentially occur in human female HCC samples, which results in decreased binding of FOXA2 and ER [123]. These results point out the following major issues to be further addressed in the FOX field: (i) context-dependency of FOX functions during carcinogenesis; and (ii) genomics and genetics focusing on the FOX-binding sites. FOXA1 and FOXP1 are bi-functional cancer-associated genes, which are oncogenic or tumor suppressive in a context-dependent manner as mentioned above. In contrast, other classes of cancerassociated genes are consistently oncogenic or tumor suppressive: MYC, MYCN and GLI1 genes, encoding transcription factors involved in cell-cycle progression and anti-apoptosis, are oncogenic [53,124,125]; TP53 and RB genes, encoding transcription factors involved in cell-cycle arrest and apoptosis, are tumor suppressive [126,127]. FOXA1 is a pioneer factor to open up chromatin for tissue-specific transcription factors, such as ER and AR. FOXA1 is involved in the transcriptional regulation of target genes of tumortype specific transcription factors that bind to the neighboring regions of FOXA1-binding sites. Because it is hypothesized that FOXA1 functions as a pioneer factor due to the structural similarity between the FOX domain and histon, there is a possibility that other FOX family members also function as pioneer factors. FOXM1 and FOXOs are preferentially oncogenic and tumor suppressive, respectively; however, these FOXs might also be bi-functional cancer-associated genes. Therefore, oncogenic as well as tumor suppressive functions of all FOX family members should be comprehensively investigated in various types of human cancers. FOX-targeted therapeutics is also a hot issue. High-throughput cell-based assay is utilized for the screening of small-molecule compounds targeted to the oncogenic FOX family members. Siomycin A and thiostrepton inhibit growth of tumor cells with FOXM1 activation through downregulation of FOXM1 expression and transcriptional repression of FOXM1-target genes [128,129]. Docking simulation software is applicable for in silico screening of small-molecule compounds directly binding to the FOX domain of FOXA1 protein using its three-dimensional structure. However, small-molecule compounds targeted FOXA1 might not be suitable for clinical application owing to the context-dependent functions of the FOXA1 as mentioned above. Because small-molecule inhibitors of ER and AR are in the clinical use for breast cancer and prostate cancer, respectively, it would be more appropriate and reasonable to target tissue-specific transcription factors co-operating with the FOXA1 pioneer factor. Recent innovations in both sequencing and information technologies [130] have drastically changed modern science, especially

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