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: www.elsevier.com/locate/canlet

Mini-review

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. http://dx.doi.org/10.1016/j.canlet.2012.09.017

Please cite this article in press as: M. Katoh et al., Cancer genetics and genomics of human FOX family genes, Cancer Lett. (2012), http://dx.doi.org/10.1016/ j.canlet.2012.09.017

2

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

FOXA1

14q21.1

FOXA2 FOXA3 FOXB1 FOXB2 FOXC1 FOXC2 FOXD1 FOXD2 FOXD3 FOXD4 FOXD4L1 FOXD4L2 FOXD4L3 FOXD4L4 FOXD4L5 FOXD4L6 FOXE1

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

FOXE3 FOXF1 FOXF2 FOXG1 FOXH1 FOXI1 FOXI2 FOXI3 FOXJ1 FOXJ2 FOXJ3 FOXK1 FOXK2 FOXL1 FOXL2 FOXM1 FOXN1 FOXN2 FOXN3 FOXN4 FOXO1

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

FOXO2 FOXO3

1p34.2 6q21

FOXO4 FOXP1

Xq13.1 3p13

FOXP2 FOXP3

7q31.1 Xp11.23

FOXP4 FOXQ1 FOXR1 FOXR2 FOXS1

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,

Please cite this article in press as: M. Katoh et al., Cancer genetics and genomics of human FOX family genes, Cancer Lett. (2012), http://dx.doi.org/10.1016/ j.canlet.2012.09.017

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

FOXA

Open chromatin

TF

FOXA

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.

3

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].

Please cite this article in press as: M. Katoh et al., Cancer genetics and genomics of human FOX family genes, Cancer Lett. (2012), http://dx.doi.org/10.1016/ j.canlet.2012.09.017

4

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

FAT

Hypoxia

Growth factor

Hedgehog

Smoothened

Patched RTK

RAS

RAF

MAP2K

YAP

α HIF1α

FOXM1

GLI

ERK

P FOXM1

TEAD FOXM1 gene

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.

Please cite this article in press as: M. Katoh et al., Cancer genetics and genomics of human FOX family genes, Cancer Lett. (2012), http://dx.doi.org/10.1016/ j.canlet.2012.09.017

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

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

5

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

Please cite this article in press as: M. Katoh et al., Cancer genetics and genomics of human FOX family genes, Cancer Lett. (2012), http://dx.doi.org/10.1016/ j.canlet.2012.09.017

6

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

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

cancer research. Whole-genome sequencing data from tens of thousands of human cancers will reveal the mutational landscape of FOX family genes themselves as well as FOX-binding sites within the regulatory regions of FOX-target genes, which could promote understanding of the mechanisms of FOX-related carcinogenesis and development of novel cancer diagnostics, prognostics and therapeutics (Fig. 3). Acknowledgements This study was supported in part by Grants-in-aids for the 3rd Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan, and the National Cancer Center Research and Development Fund. References [1] P. Carlsson, M. Mahlapuu, Forkhead transcription factors: key players in development and metabolism, Dev. Biol. 250 (2002) 1–23. [2] O.J. Lehmann, J.C. Sowden, P. Carlsson, T. Jordan, S.S. Bhattacharya, Fox’s in development and disease, Trends Genet. 19 (2003) 339–344. [3] M. Katoh, M. Katoh, Human FOX gene family, Int. J. Oncol. 25 (2004) 1495– 1500. [4] S. Hannenhalli, K.H. Kaestner, The evolution of Fox genes and their role in development and disease, Nat. Rev. Genet. 10 (2009) 233–240. [5] B.A. Benayoun, S. Caburet, R.A. Veitia, Forkhead transcription factors: key players in health and disease, Trends Genet. 27 (2011) 224–232. [6] D. Weigel, G. Jürgens, F. Küttner, E. Seifert, H. Jäckle, The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo, Cell 57 (1989) 645–658. [7] E. Lai, K.L. Clark, S.K. Burley, J.E. Darnell Jr., Hepatocyte nuclear factor 3/fork head or ‘‘winged helix’’ proteins: a family of transcription factors of diverse biologic function, Proc. Natl. Acad. Sci. USA 90 (1993) 10421–10423. [8] K.L. Clark, E.D. Halay, E. Lai, S.K. Burley, Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5, Nature 364 (1993) 412– 420. [9] M.J. van Dongen, A. Cederberg, P. Carlsson, S. Enerback, M. Wikstrom, Solution structure and dynamics of the DNA-binding domain of the adipocytetranscription factor FREAC-11, J. Mol. Biol. 296 (2000) 351–359. [10] S. Pierrou, M. Hellqvist, L. Samuelsson, S. Enerbäck, P. Carlsson, Cloning and characterization of seven human forkhead proteins: binding site specificity and DNA bending, EMBO J. 13 (1994) 5002–5012. [11] Y. Fujii, M. Nakamura, FOXK2 transcription factor is a novel G/T-mismatch DNA binding protein, J. Biochem. 147 (2010) 705–709. [12] M. Almeida, L. Han, M. Martin-Millan, C.A. O’Brien, S.C. Manolagas, Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting bcatenin from TCF- to FoxO-mediated transcription, J. Biol. Chem. 282 (2007) 27298–27305. [13] A. Roesch, A.M. Mueller, T. Stempfl, C. Moehle, M. Landthaler, T. Vogt, RBP2H1/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells, Int. J. Cancer 122 (2008) 1047–1057. [14] A.B. Brenkman, N.J. van den Broek, P.L. de Keizer, D.C. van Gent, B.M. Burgering, The DNA damage repair protein Ku70 interacts with FOXO4 to coordinate a conserved cellular stress response, FASEB J. 24 (2010) 4271– 4280. [15] S.E. Fisher, C. Scharff, FOXP2 as a molecular window into speech and language, Trends Genet. 25 (2009) 166–177.

Please cite this article in press as: M. Katoh et al., Cancer genetics and genomics of human FOX family genes, Cancer Lett. (2012), http://dx.doi.org/10.1016/ j.canlet.2012.09.017

M. Katoh et al. / Cancer Letters xxx (2012) xxx–xxx [16] D.F. Newbury, A.P. Monaco, Genetic advances in the study of speech and language disorders, Neuron 68 (2010) 309–320. [17] P. Stankiewicz, P. Sen, S.S. Bhatt, M. Storer, Z. Xia, B.A. Bejjani, Z. Ou, J. Wiszniewska, D.J. Driscoll, M.K. Maisenbacher, J. Bolivar, M. Bauer, et al., Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations, Am. J. Hum. Genet. 84 (2009) 780–791. [18] A.K. Manning, M.F. Hivert, R.A. Scott, J.L. Grimsby, N. Bouatia-Naji, H. Chen, D. Rybin, C.T. Liu, L.F. Bielak, I. Prokopenko, N. Amin, D. Barnes, et al., A genomewide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance, Nat. Genet. 44 (2012) 659–669. [19] C.S. Li, S.C. Chae, J.H. Lee, Q. Zhang, H.T. Chung, Identification of single nucleotide polymorphisms in FOXJ1 and their association with allergic rhinitis, J. Hum. Genet. 51 (2006) 292–297. [20] B.J. Willcox, T.A. Donlon, Q. He, R. Chen, J.S. Grove, K. Yano, K.H. Masaki, D.C. Willcox, B. Rodriguez, J.D. Curb, FOXO3A genotype is strongly associated with human longevity, Proc. Natl. Acad. Sci. USA 105 (2008) 13987–13992. [21] Y. Jin, S.A. Birlea, P.R. Fain, C.M. Mailloux, S.L. Riccardi, K. Gowan, P.J. Holland, D.C. Bennett, M.R. Wallace, W.T. McCormack, E.H. Kemp, D.J. Gawkrodger, et al., Common variants in FOXP1 are associated with generalized vitiligo, Nat. Genet. 42 (2010) 576–578. [22] Y. Böttcher, A. Tönjes, B. Enigk, G.H. Scholz, M. Blüher, M. Stumvoll, P. Kovacs, A SNP haplotype of the forkhead transcription factor FOXO1A gene may have a protective effect against type 2 diabetes in German Caucasians, Diabetes Metab. 33 (2007) 277–283. [23] K. Müssig, H. Staiger, F. Machicao, A. Stancáková, J. Kuusisto, M. Laakso, C. Thamer, J. Machann, F. Schick, C.D. Claussen, N. Stefan, A. Fritsche, et al., Association of common genetic variation in the FOXO1 gene with b-cell dysfunction, impaired glucose tolerance, and type 2 diabetes, J. Clin. Endocrinol. Metab. 94 (2009) 1353–1360. [24] E.R. Fearon, B. Vogelstein, A genetic model for colorectal tumorigenesis, Cell 61 (1990) 759–767. [25] M. Katoh, Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer, Cancer Biol. Ther. 6 (2007) 832–839. [26] S.B. Baylin, P.A. Jones, A decade of exploring the cancer epigenome – biological and translational implications, Nat. Rev. Cancer 11 (2011) 726–734. [27] X. Sagaert, C. de Wolf-Peeters, H. Noels, M. Baens, The pathogenesis of MALT lymphomas: where do we stand?, Leukemia 21 (2007) 389–396 [28] S.S. Myatt, E.W. Lam, The emerging roles of forkhead box (Fox) proteins in cancer, Nat. Rev. Cancer 7 (2007) 847–859. [29] T.B. Dansen, B.M. Burgering, Unravelling the tumor-suppressive functions of FOXO proteins, Trends Cell Biol. 18 (2008) 421–429. [30] L. Lin, C.T. Miller, J.I. Contreras, M.S. Prescott, S.L. Dagenais, R. Wu, J. Yee, M.B. Orringer, D.E. Misek, S.M. Hanash, T.W. Glover, D.G. Beer, The hepatocyte nuclear factor 3 a gene, HNF3a (FOXA1), on chromosome band 14q13 is amplified and overexpressed in esophageal and lung adenocarcinomas, Cancer Res. 62 (2002) 5273–5279. [31] X. Hu, H.M. Stern, L. Ge, C. O’Brien, L. Haydu, C.D. Honchell, P.M. Haverty, B.A. Peters, T.D. Wu, L.C. Amler, J. Chant, D. Stokoe, et al., Genetic alterations and oncogenic pathways associated with breast cancer subtypes, Mol. Cancer Res. 7 (2009) 511–522. [32] C. Nucera, J. Eeckhoute, S. Finn, J.S. Carroll, A.H. Ligon, C. Priolo, G. Fadda, M. Toner, O. Sheils, M. Attard, A. Pontecorvi, V. Nose, et al., FOXA1 is a potential oncogene in anaplastic thyroid carcinoma, Clin. Cancer Res. 15 (2009) 3680– 3689. [33] C.M. Robbins, W.A. Tembe, A. Baker, S. Sinari, T.Y. Moses, S. BeckstromSternberg, J. Beckstrom-Sternberg, M. Barrett, J. Long, A. Chinnaiyan, J. Lowey, E. Suh, et al., Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors, Genome Res. 21 (2011) 47–55. [34] C.S. Grasso, Y.M. Wu, D.R. Robinson, X. Cao, S.M. Dhanasekaran, A.P. Khan, M.J. Quist, X. Jing, R.J. Lonigro, J.C. Brenner, I.A. Asangani, B. Ateeq, et al., The mutational landscape of lethal castration-resistant prostate cancer, Nature, in press. [35] C. Curtis, S.P. Shah, S.F. Chin, G. Turashvili, O.M. Rueda, M.J. Dunning, D. Speed, A.G. Lynch, S. Samarajiwa, Y. Yuan, S. Gräf, G. Ha, et al., The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups, Nature 486 (2012) 346–352. [36] J. Laganière, G. Deblois, C. Lefebvre, A.R. Bataille, F. Robert, V. Giguère, From the cover: location analysis of estrogen receptor a target promoters reveals that FOXA1 defines a domain of the estrogen response, Proc. Natl. Acad. Sci. USA 102 (2005) 11651–11656. [37] J. Schneider, M. Ruschhaupt, A. Buness, M. Asslaber, P. Regitnig, K. Zatloukal, W. Schippinger, F. Ploner, A. Poustka, H. Sültmann, Identification and metaanalysis of a small gene expression signature for the diagnosis of estrogen receptor status in invasive ductal breast cancer, Int. J. Cancer 119 (2006) 2974–2979. [38] L. van der Heul-Nieuwenhuijsen, N.F. Dits, G. Jenster, Gene expression of forkhead transcription factors in the normal and diseased human prostate, BJU Int. 103 (2009) 1574–1580. [39] J.R. Friedman, K.H. Kaestner, The Foxa family of transcription factors in development and metabolism, Cell. Mol. Life Sci. 63 (2006) 2317–2328. [40] L.A. Cirillo, F.R. Lin, I. Cuesta, D. Friedman, M. Jarnik, K.S. Zaret, Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4, Mol. Cell 9 (2002) 279–289.

7

[41] T. Sekiya, U.M. Muthurajan, K. Luger, A.V. Tulin, K.S. Zaret, Nucleosomebinding affinity as a primary determinant of the nuclear mobility of the pioneer transcription factor FoxA, Genes Dev. 23 (2009) 804–809. [42] H. Hirai, T. Tani, N. Kikyo, Structure and functions of powerful transactivators: VP16, MyoD and FoxA, Int. J. Dev. Biol. 54 (2010) 1589–1596. [43] A.A. Sérandour, S. Avner, F. Percevault, F. Demay, M. Bizot, C. LucchettiMiganeh, F. Barloy-Hubler, M. Brown, M. Lupien, R. Métivier, G. Salbert, J. Eeckhoute, Epigenetic switch involved in activation of pioneer factor FOXA1dependent enhancers, Genome Res. 21 (2011) 555–565. [44] K.S. Zaret, J. Watts, J. Xu, E. Wandzioch, S.T. Smale, T. Sekiya, Pioneer factors, genetic competence, and inductive signaling: programming liver and pancreas progenitors from the endoderm, Cold Spring Harb. Symp. Quant. Biol. 73 (2008) 119–126. [45] L. Magnani, J. Eeckhoute, M. Lupien, Pioneer factors: directing transcriptional regulators within the chromatin environment, Trends Genet. 27 (2011) 465– 474. [46] N. Gao, J. Zhang, M.A. Rao, T.C. Case, J. Mirosevich, Y. Wang, R. Jin, A. Gupta, P.S. Rennie, R.J. Matusik, The role of hepatocyte nuclear factor-3 a (Forkhead Box A1) and androgen receptor in transcriptional regulation of prostatic genes, Mol. Endocrinol. 17 (2003) 1484–1507. [47] C. Zhang, L. Wang, D. Wu, H. Chen, Z. Chen, J.M. Thomas-Ahner, D.L. Zynger, J. Eeckhoute, J. Yu, J. Luo, M. Brown, S.K. Clinton, et al., Definition of a FoxA1 cistrome that is crucial for G1 to S-phase cell-cycle transit in castrationresistant prostate cancer, Cancer Res. 71 (2011) 6738–6748. [48] M.A. Thorat, C. Marchio, A. Morimiya, K. Savage, H. Nakshatri, J.S. Reis-Filho, S. Badve, Forkhead box A1 expression in breast cancer is associated with luminal subtype and good prognosis, J. Clin. Pathol. 61 (2008) 327–332. [49] B. Sahu, M. Laakso, K. Ovaska, T. Mirtti, J. Lundin, A. Rannikko, A. Sankila, J.P. Turunen, M. Lundin, J. Konsti, T. Vesterinen, S. Nordling, et al., Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer, EMBO J. 30 (2011) 3962–3976. [50] M.R. Green, C. Aya-Bonilla, M.K. Gandhi, R.A. Lea, J. Wellwood, P. Wood, P. Marlton, L.R. Griffiths, Integrative genomic profiling reveals conserved genetic mechanisms for tumorigenesis in common entities of nonHodgkin’s lymphoma, Genes Chromosom. Cancer 50 (2011) 313–326. [51] J. Yu, H. Deshmukh, J.E. Payton, C. Dunham, B.W. Scheithauer, T. Tihan, R.A. Prayson, A. Guha, J.A. Bridge, R.E. Ferner, G.M. Lindberg, R.J. Gutmann, et al., Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor, Clin. Cancer Res. 17 (2011) 1924–1934. [52] M.T. Teh, S.T. Wong, G.W. Neill, L.R. Ghali, M.P. Philpott, A.G. Quinn, FOXM1 is a downstream target of Gli1 in basal cell carcinomas, Cancer Res. 62 (2002) 4773–4780. [53] Y. Katoh, M. Katoh, Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation, Curr. Mol. Med. 9 (2009) 873–886. [54] L.M. Xia, W.J. Huang, B. Wang, M. Liu, Q. Zhang, W. Yan, Q. Zhu, M. Luo, Z.Z. Zhou, D.A. Tian, Transcriptional up-regulation of FoxM1 in response to hypoxia is mediated by HIF-1, J. Cell. Biochem. 106 (2009) 247–256. [55] T. Mizuno, H. Murakami, M. Fujii, F. Ishiguro, I. Tanaka, Y. Kondo, S. Akatsuka, S. Toyokuni, K. Yokoi, H. Osada, Y. Sekido, YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cyclepromoting genes, Oncogene, in press. [56] Y. Chen, B. Zheng, D.H. Robbins, D.N. Lewin, K. Mikhitarian, A. Graham, L. Rumpp, T. Glenn, W.E. Gillanders, D.J. Cole, X. Lu, B.J. Hoffman, et al., Accurate discrimination of pancreatic ductal adenocarcinoma and chronic pancreatitis using multimarker expression data and samples obtained by minimally invasive fine needle aspiration, Int. J. Cancer 120 (2007) 1511–1517. [57] D.W. Chan, S.Y. Yu, P.M. Chiu, K.M. Yao, V.W. Liu, A.N. Cheung, H.Y. Ngan, Over-expression of FOXM1 transcription factor is associated with cervical cancer progression and pathogenesis, J. Pathol. 215 (2008) 245–252. [58] E. Gemenetzidis, A. Bose, A.M. Riaz, T. Chaplin, B.D. Young, M. Ali, D. Sugden, J.K. Thurlow, S.C. Cheong, S.H. Teo, H. Wan, A. Waseem, et al., FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation, PLoS One 4 (2009) e4849. [59] D.K. Yang, C.H. Son, S.K. Lee, P.J. Choi, K.E. Lee, M.S. Roh, Forkhead box M1 expression in pulmonary squamous cell carcinoma: correlation with clinicopathologic features and its prognostic significance, Hum. Pathol. 40 (2009) 464–470. [60] M. Lin, L.M. Guo, H. Liu, J. Du, J. Yang, L.J. Zhang, B. Zhang, Nuclear accumulation of glioma-associated oncogene 2 protein and enhanced expression of forkhead-box transcription factor M1 protein in human hepatocellular carcinoma, Histol. Histopathol. 25 (2010) 1269–1275. [61] M. Priller, J. Pöschl, L. Abrão, A.O. von Bueren, Y.J. Cho, S. Rutkowski, H.A. Kretzschmar, U. Schüller, Expression of FoxM1 is required for the proliferation of medulloblastoma cells and indicates worse survival of patients, Clin. Cancer Res. 17 (2011) 6791–6801. [62] G. Pignot, A. Vieillefond, S. Vacher, M. Zerbib, B. Debre, R. Lidereau, D. Amsellem-Ouazana, I. Bieche, Hedgehog pathway activation in human transitional cell carcinoma of the bladder, Br. J. Cancer 106 (2012) 1177– 1186. [63] R.Y. Ma, T.H. Tong, A.M. Cheung, A.C. Tsang, W.Y. Leung, K.M. Yao, Raf/MEK/ MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c, J. Cell Sci. 118 (2005) 795–806.

Please cite this article in press as: M. Katoh et al., Cancer genetics and genomics of human FOX family genes, Cancer Lett. (2012), http://dx.doi.org/10.1016/ j.canlet.2012.09.017

8

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

[64] I.C. Wang, Y.J. Chen, D. Hughes, V. Petrovic, M.L. Major, H.J. Park, Y. Tan, T. Ackerson, R.H. Costa, Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2Cks1) ubiquitin ligase, Mol. Cell. Biol. 25 (2005) 10875–10894. [65] A. Ahmad, Z. Wang, D. Kong, S. Ali, Y. Li, S. Banerjee, R. Ali, F.H. Sarkar, FoxM1 down-regulation leads to inhibition of proliferation, migration and invasion of breast cancer cells through the modulation of extra-cellular matrix degrading factors, Breast Cancer Res. Treat. 122 (2010) 337–346. [66] Z. Wang, A. Ahmad, Y. Li, S. Banerjee, D. Kong, F.H. Sarkar, Forkhead box M1 transcription factor: a novel target for cancer therapy, Cancer Treat. Rev. 36 (2010) 151–156. [67] K.M. Huynh, J.W. Soh, R. Dash, D. Sarkar, P.B. Fisher, D. Kang, FOXM1 expression mediates growth suppression during terminal differentiation of HO-1 human metastatic melanoma cells, J. Cell. Physiol. 226 (2011) 194–204. [68] B. Bao, Z. Wang, S. Ali, D. Kong, S. Banerjee, A. Ahmad, Y. Li, A.S. Azmi, L. Miele, F.H. Sarkar, Over-expression of FoxM1 leads to epithelial–mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells, J. Cell. Biochem. 112 (2011) 2296–2306. [69] D. Frescas, M. Pagano, Deregulated proteolysis by the F-box proteins SKP2 and b-TrCP: tipping the scales of cancer, Nat. Rev. Cancer 8 (2008) 438–449. [70] J.T. Xia, H. Wang, L.J. Liang, B.G. Peng, Z.F. Wu, L.Z. Chen, L. Xue, Z. Li, W. Li, Overexpression of FOXM1 is associated with poor prognosis and clinicopathologic stage of pancreatic ductal adenocarcinoma, Pancreas 41 (2012) 629–635. [71] S. Reagan-Shaw, N. Ahmad, The role of Forkhead-box Class O (FoxO) transcription factors in cancer: a target for the management of cancer, Toxicol. Appl. Pharmacol. 224 (2007) 360–368. [72] X.Y. Dong, C. Chen, X. Sun, P. Guo, R.L. Vessella, R.X. Wang, L.W. Chung, W. Zhou, J.T. Dong, FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer, Cancer Res. 66 (2006) 6998–7006. [73] L. Yang, H.M. Hu, A. Zielinska-Kwiatkowska, H.A. Chansky, FOXO1 is a direct target of EWS-Fli1 oncogenic fusion protein in Ewing’s sarcoma cells, Biochem. Biophys. Res. Commun. 402 (2010) 129–134. [74] X. Liu, Z. Zhang, L. Sun, N. Chai, S. Tang, J. Jin, H. Hu, Y. Nie, X. Wang, K. Wu, et al., MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4, Carcinogenesis 32 (2011) 1798–1805. [75] P.O. Hasselgren, Ubiquitination, phosphorylation, and acetylation – triple threat in muscle wasting, J. Cell. Physiol. 213 (2007) 679–689. [76] J.Y. Yang, M.C. Hung, A new fork for clinical application: targeting forkhead transcription factors in cancer, Clin. Cancer Res. 15 (2009) 752–757. [77] R. Lüpertz, Y. Chovolou, K. Unfried, A. Kampkötter, W. Wätjen, R. Kahl, The forkhead transcription factor FOXO4 sensitizes cancer cells to doxorubicinmediated cytotoxicity, Carcinogenesis 29 (2008) 2045–2052. [78] A. Polter, S. Yang, A.A. Zmijewska, T. van Groen, J.H. Paik, R.A. Depinho, S.L. Peng, R.S. Jope, X. Li, Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation, Biol. Psychiatry 65 (2009) 150–159. [79] A.A. Szypowska, H. de Ruiter, L.A. Meijer, L.M. Smits, B.M. Burgering, Oxidative stress-dependent regulation of Forkhead box O4 activity by nemo-like kinase, Antioxid. Redox Signal. 14 (2011) 563–578. [80] W. Fu, Q. Ma, L. Chen, P. Li, M. Zhang, S. Ramamoorthy, Z. Nawaz, T. Shimojima, H. Wang, Y. Yang, Z. Shen, Y. Zhang, et al., MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation, J. Biol. Chem. 284 (2009) 13987–14000. [81] A. Oteiza, N. Mechti, The human T-cell leukemia virus type 1 oncoprotein tax controls forkhead box O4 activity through degradation by the proteasome, J. Virol. 85 (2011) 6480–6491. [82] J. Momand, D. Jung, S. Wilczynski, J. Niland, The MDM2 gene amplification database, Nucleic Acids Res. 26 (1998) 3453–3459. [83] B. Streubel, U. Vinatzer, A. Lamprecht, M. Raderer, A. Chott, T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma, Leukemia 19 (2005) 652–658. [84] C.G. Mullighan, S. Goorha, I. Radtke, C.B. Miller, E. Coustan-Smith, J.D. Dalton, K. Girtman, S. Mathew, J. Ma, S.B. Pounds, X. Su, C.H. Pui, et al., Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia, Nature 446 (2007) 758–764. [85] T. Ernst, J. Score, M. Deininger, C. Hidalgo-Curtis, P. Lackie, W.B. Ershler, J.M. Goldman, N.C. Cross, F. Grand, Identification of FOXP1 and SNX2 as novel ABL1 fusion partners in acute lymphoblastic leukaemia, Br. J. Haematol. 153 (2011) 43–46. [86] K.G. Hermans, H.A. van der Korput, R. van Marion, D.J. van de Wijngaart, A. Ziel-van der Made, N.F. Dits, J.L. Boormans, T.H. van der Kwast, H. van Dekken, C.H. Bangma, H. Korsten, R. Kraaij, et al., Truncated ETV1, fused to novel tissue-specific genes, and full-length ETV1 in prostate cancer, Cancer Res. 68 (2008) 7541–7549. [87] A. Goatly, C.M. Bacon, S. Nakamura, H. Ye, I. Kim, P.J. Brown, A. RuskonéFourmestraux, P. Cervera, B. Streubel, A.H. Banham, M.Q. Du, FOXP1 abnormalities in lymphoma: translocation breakpoint mapping reveals insights into deregulated transcriptional control, Mod. Pathol. 21 (2008) 902–911. [88] T. Klampfl, A. Harutyunyan, T. Berg, B. Gisslinger, M. Schalling, K. Bagienski, D. Olcaydu, F. Passamonti, E. Rumi, D. Pietra, R. Jäger, L. Pieri, et al., Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression, Blood 118 (2011) 167–176.

[89] M.I. Toma, M. Grosser, A. Herr, D.E. Aust, A. Meye, C. Hoefling, S. Fuessel, D. Wuttig, M.P. Wirth, G.B. Baretton, Loss of heterozygosity and copy number abnormality in clear cell renal cell carcinoma discovered by high-density affymetrix 10K single nucleotide polymorphism mapping array, Neoplasia 10 (2008) 634–642. [90] A.H. Banham, N. Beasley, E. Campo, P.L. Fernandez, C. Fidler, K. Gatter, M. Jones, D.Y. Mason, J.E. Prime, P. Trougouboff, K. Wood, J.L. Cordell, The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p, Cancer Res. 61 (2001) 8820–8829. [91] M.H. Yang, B.R. Lin, C.H. Chang, S.T. Chen, S.K. Lin, M.Y. Kuo, Y.M. Jeng, M.L. Kuo, C.C. Chang, Connective tissue growth factor modulates oral squamous cell carcinoma invasion by activating a miR-504/FOXP1 signalling, Oncogene 31 (2012) 2401–2411. [92] V.J. Craig, S.B. Cogliatti, J. Imig, C. Renner, S. Neuenschwander, H. Rehrauer, R. Schlapbach, S. Dirnhofer, A. Tzankov, A. Müller, Myc-mediated repression of microRNA-34a promotes high-grade transformation of B-cell lymphoma by dysregulation of FoxP1, Blood 117 (2011) 6227–6236. [93] J. Datta, H. Kutay, M.W. Nasser, G.J. Nuovo, B. Wang, S. Majumder, C.G. Liu, S. Volinia, C.M. Croce, T.D. Schmittgen, K. Ghoshal, S.T. Jacob, Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis, Cancer Res. 68 (2008) 5049–5058. [94] Y. Zhang, S. Li, L. Yuan, Y. Tian, J. Weidenfeld, J. Yang, F. Liu, A.L. Chokas, E.E. Morrisey, Foxp1 coordinates cardiomyocyte proliferation through both cellautonomous and nonautonomous mechanisms, Genes Dev. 24 (2010) 1746– 1757. [95] H. Hu, B. Wang, M. Borde, J. Nardone, S. Maika, L. Allred, P.W. Tucker, A. Rao, Foxp1 is an essential transcriptional regulator of B cell development, Nat. Immunol. 7 (2006) 819–826. [96] H.B. Koon, G.C. Ippolito, A.H. Banham, P.W. Tucker, FOXP1: a potential therapeutic target in cancer, Expert Opin Ther. Targets 11 (2007) 955–965. [97] S.L. Barrans, J.A. Fenton, A. Banham, R.G. Owen, A.S. Jack, Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome, Blood 104 (2004) 2933–2935. [98] S.L. Han, X.L. Wu, L. Wan, Q.Q. Zeng, J.L. Li, Z. Liu, FOXP1 expression predicts polymorphic histology and poor prognosis in gastric mucosa-associated lymphoid tissue lymphomas, Dig. Surg. 26 (2009) 156–162. [99] Y. Zhang, S. Zhang, X. Wang, J. Liu, L. Yang, S. He, L. Chen, J. Huang, Prognostic significance of FOXP1 as an oncogene in hepatocellular carcinoma, J. Clin. Pathol. 65 (2012) 528–533. [100] S.B. Fox, P. Brown, C. Han, S. Ashe, R.D. Leek, A.L. Harris, A.H. Banham, Expression of the forkhead transcription factor FOXP1 is associated with estrogen receptor a and improved survival in primary human breast carcinomas, Clin. Cancer Res. 10 (2004) 3521–3527. [101] M. Katoh, M. Katoh, Identification and characterization of human FOXN5 and rat Foxn5 genes in silico, Int. J. Oncol. 24 (2004) 1339–1344. [102] E.E. Santo, M.E. Ebus, J. Koster, J.H. Schulte, A. Lakeman, P. van Sluis, J. Vermeulen, D. Gisselsson, I. Øra, S. Lindner, P.G. Buckley, R.L. Stallings, et al., Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion–fusions in neuroblastoma, Oncogene 31 (2012) 1571–1581. [103] S.A. Mani, J. Yang, M. Brooks, G. Schwaninger, A. Zhou, N. Miura, J.L. Kutok, K. Hartwell, A.L. Richardson, R.A. Weinberg, Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers, Proc. Natl. Acad. Sci. USA 104 (2007) 10069–10074. [104] Y. Xue, R. Cao, D. Nilsson, S. Chen, R. Westergren, E.M. Hedlund, C. Martijn, L. Rondahl, P. Krauli, E. Walum, S. Enerbäck, Y. Cao, FOXC2 controls Ang-2 expression and modulates angiogenesis, vascular patterning, remodeling, and functions in adipose tissue, Proc. Natl. Acad. Sci. USA 105 (2008) 10167– 10172. [105] Y. Li, W. Yang, Q. Yang, S. Zhou, Nuclear localization of GLI1 and elevated expression of FOXC2 in breast cancer is associated with the basal-like phenotype, Histol. Histopathol. 27 (2012) 475–484. [106] N. Nishida, K. Mimori, T. Yokobori, T. Sudo, F. Tanaka, K. Shibata, H. Ishii, Y. Doki, M. Mori, FOXC2 is a novel prognostic factor in human esophageal squamous cell carcinoma, Ann. Surg. Oncol. 18 (2011) 535–542. [107] I. Cuesta, K.S. Zaret, P. Santisteban, The forkhead factor FoxE1 binds to the thyroperoxidase promoter during thyroid cell differentiation and modifies compacted chromatin structure, Mol. Cell. Biol. 27 (2007) 7302–7314. [108] I. Landa, S. Ruiz-Llorente, C. Montero-Conde, L. Inglada-Pérez, F. Schiavi, S. Leskelä, G. Pita, R. Milne, J. Maravall, I. Ramos, V. Andía, P. Rodríguez-Poyo, et al., The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors, PLoS Genet. 5 (2009) e1000637. [109] I. Venza, M. Visalli, B. Tripodo, G. de Grazia, S. Loddo, D. Teti, M. Venza, FOXE1 is a target for aberrant methylation in cutaneous squamous cell carcinoma, Br. J. Dermatol. 162 (2010) 1093–1097. [110] A. Brancaccio, A. Minichiello, M. Grachtchouk, D. Antonini, H. Sheng, R. Parlato, N. Dathan, A.A. Dlugosz, C. Missero, Requirement of the forkhead gene Foxe1, a target of sonic hedgehog signaling, in hair follicle morphogenesis, Hum. Mol. Genet. 13 (2004) 2595–2606. [111] J.E. Watson, N.A. Doggett, D.G. Albertson, A. Andaya, A. Chinnaiyan, H. van Dekken, D. Ginzinger, C. Haqq, K. James, S. Kamkar, D. Kowbel, D. Pinkel, et al., Integration of high-resolution array comparative genomic hybridization analysis of chromosome 16q with expression array data refines common regions of loss at 16q23-qter and identifies underlying candidate tumor suppressor genes in prostate cancer, Oncogene 23 (2004) 3487–3494.

Please cite this article in press as: M. Katoh et al., Cancer genetics and genomics of human FOX family genes, Cancer Lett. (2012), http://dx.doi.org/10.1016/ j.canlet.2012.09.017

M. Katoh et al. / Cancer Letters xxx (2012) xxx–xxx [112] P.K. Lo, J.S. Lee, X. Liang, L. Han, T. Mori, M.J. Fackler, H. Sadik, P. Argani, T.K. Pandita, S. Sukumar, Epigenetic inactivation of the potential tumor suppressor gene FOXF1 in breast cancer, Cancer Res. 70 (2010) 6047–6058. [113] P.K. Lo, J.S. Lee, S. Sukumar, The p53–p21WAF1 checkpoint pathway plays a protective role in preventing DNA rereplication induced by abrogation of FOXF1 function, Cell. Signal. 24 (2012) 316–324. [114] J. Nilsson, K. Helou, A. Kovács, P.O. Bendahl, G. Bjursell, M. Fernö, P. Carlsson, M. Kannius-Janson, Nuclear Janus-activated kinase 2/nuclear factor 1–C2 suppresses tumorigenesis and epithelial-to-mesenchymal transition by repressing Forkhead box F1, Cancer Res. 70 (2010) 2020–2029. [115] A. Feuerborn, P.K. Srivastava, S. Küffer, W.A. Grandy, T.P. Sijmonsma, N. Gretz, B. Brors, H.J. Gröne, The Forkhead factor FoxQ1 influences epithelial differentiation, J. Cell. Physiol. 226 (2011) 710–719. [116] H. Zhang, F. Meng, G. Liu, B. Zhang, J. Zhu, F. Wu, S.P. Ethier, F. Miller, G. Wu, Forkhead transcription factor FOXQ1 promotes epithelial–mesenchymal transition and breast cancer metastasis, Cancer Res. 71 (2011) 1292–1301. [117] Y. Qiao, X. Jiang, S.T. Lee, R.K. Karuturi, S.C. Hooi, Q. Yu, FOXQ1 regulates epithelial–mesenchymal transition in human cancers, Cancer Res. 71 (2011) 3076–3086. [118] D.J. Birnbaum, J. Adélaïde, E. Mamessier, P. Finetti, A. Lagarde, G. Monges, F. Viret, A. Gonçalvès, O. Turrini, J.R. Delpero, J. Iovanna, M. Giovannini, et al., Genome profiling of pancreatic adenocarcinoma, Genes Chromosom. Cancer 50 (2011) 456–465. [119] A.M. Adesina, Y. Nguyen, P. Guanaratne, J. Pulliam, D. Lopez-Terrada, J. Margolin, M. Finegold, FOXG1 is overexpressed in hepatoblastoma, Hum. Pathol. 38 (2007) 400–409. [120] S.P. Shah, M. Köbel, J. Senz, R.D. Morin, B.A. Clarke, K.C. Wiegand, G. Leung, A. Zayed, E. Mehl, S.E. Kalloger, M. Sun, R. Giuliany, et al., Mutation of FOXL2

[121]

[122]

[123] [124] [125] [126] [127] [128]

[129]

[130]

9

in granulosa-cell tumors of the ovary, N. Engl. J. Med. 360 (2009) 2719–2729. T. Zuo, L. Wang, C. Morrison, X. Chang, H. Zhang, W. Li, Y. Liu, Y. Wang, X. Liu, M.W. Chan, J.Q. Liu, R. Love, et al., FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene, Cell 129 (2007) 1275–1286. L. Wang, R. Liu, W. Li, C. Chen, H. Katoh, G.Y. Chen, B. McNally, L. Lin, P. Zhou, T. Zuo, K.A. Cooney, Y. Liu, et al., Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate, Cancer Cell 16 (2009) 336–346. Z. Li, G. Tuteja, J. Schug, K.H. Kaestner, Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer, Cell 148 (2012) 72–83. F. Westermann, M. Schwab, Genetic parameters of neuroblastomas, Cancer Lett. 184 (2002) 127–147. M. Eilers, R.N. Eisenman, Myc’s broad reach, Genes Dev. 22 (2008) 2755– 2766. A.J. Levine, M. Oren, The first 30 years of p53: growing ever more complex, Nat. Rev. Cancer 9 (2009) 749–758. D.L. Burkhart, J. Sage, Cellular mechanisms of tumour suppression by the retinoblastoma gene, Nat. Rev. Cancer 8 (2008) 671–682. S.K. Radhakrishnan, U.G. Bhat, D.E. Hughes, I.C. Wang, R.H. Costa, A.L. Gartel, Identification of a chemical inhibitor of the oncogenic transcription factor forkhead box M1, Cancer Res. 66 (2006) 9731–9735. M. Wang, A.L. Gartel, Micelle-encapsulated thiostrepton as an effective nanomedicine for inhibiting tumor growth and for suppressing FOXM1 in human xenografts, Mol. Cancer Ther. 10 (2011) 2287–2297. S. Koren, M.C. Schatz, B.P. Walenz, J. Martin, J.T. Howard, G. Ganapathy, Z. Wang, D.A. Rasko, W.R. McCombie, E.D. Jarvis, A.M. Phillippy, Hybrid error correction and de novo assembly of single-molecule sequencing reads, Nat. Biotechnol. 30 (2012) 693–700.

Please cite this article in press as: M. Katoh et al., Cancer genetics and genomics of human FOX family genes, Cancer Lett. (2012), http://dx.doi.org/10.1016/ j.canlet.2012.09.017