Forkhead box proteins: tuning forks for transcriptional harmony (original) (raw)

• Myatt, S. S. & Lam, E. W. The emerging roles of forkhead box (Fox) proteins in cancer. Nature Rev. Cancer 7, 847–859 (2007).
  Article CAS Google Scholar
• Weigel, D., Jurgens, G., Kuttner, F., Seifert, E. & Jackle, H. The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo. Cell 57, 645–658 (1989).
  Article CAS PubMed Google Scholar
• Jackson, B. C., Carpenter, C., Nebert, D. W. & Vasiliou, V. Update of human and mouse forkhead box (FOX) gene families. Hum. Genomics 4, 345–352 (2010). A recent survey of all human and mouse FOX genes.
  CAS PubMed PubMed Central Google Scholar
• Kaestner, K. H., Knochel, W. & Martinez, D. E. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev. 14, 142–146 (2000).
  CAS PubMed Google Scholar
• McGovern, U. B. et al. Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer. Mol. Cancer Ther. 8, 582–591 (2009).
  Article CAS PubMed Google Scholar
• Francis, R. E. et al. FoxM1 is a downstream target and marker of HER2 overexpression in breast cancer. Int. J. Oncol. 35, 57–68 (2009).
  CAS PubMed Google Scholar
• Karadedou, C. T. et al. FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer. Oncogene 31, 1845–1858 (2012). This work describes the mechanisms by which FOXO3A and FOXM1 antagonize the activity of one another and regulate common target gene expression.
  Article CAS PubMed Google Scholar
• Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Calnan, D. R. & Brunet, A. The FoxO code. Oncogene 27, 2276–2288 (2008).
  Article CAS PubMed Google Scholar
• Smith, G. R. & Shanley, D. P. Modelling the response of FOXO transcription factors to multiple post-translational modifications made by ageing-related signalling pathways. PLoS ONE 5, e11092 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, Y., Wang, L., Han, R., Beier, U. H. & Hancock, W. W. Two lysines in the forkhead domain of foxp3 are key to T regulatory cell function. PLoS ONE 7, e29035 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Jacobs, F. M. et al. FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J. Biol. Chem. 278, 35959–35967 (2003).
  Article CAS PubMed Google Scholar
• Lee, E. J., Kim, J. M., Lee, M. K. & Jameson, J. L. Splice variants of the forkhead box protein AFX exhibit dominant negative activity and inhibit AFXα-mediated tumor cell apoptosis. PLoS ONE 3, e2743 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Paik, J. H. et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309–323 (2007). A seminal study examining the role of individual FOXO proteins in tumour suppression and identifying functional redundancy between family members for the first time.
  Article CAS PubMed PubMed Central Google Scholar
• Dong, X. Y. et al. FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer. Cancer Res. 66, 6998–7006 (2006).
  Article CAS PubMed Google Scholar
• Yang, J. Y. et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nature Cell Biol. 10, 138–148 (2008).
  Article CAS PubMed Google Scholar
• Hu, M. C. et al. IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117, 225–237 (2004).
  Article CAS PubMed Google Scholar
• Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999). This article suggests a model for FOXO protein phosphorylation and regulation by AKT.
  Article CAS PubMed Google Scholar
• Brunet, A. et al. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol. Cell. Biol. 21, 952–965 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Huang, H. et al. Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc. Natl Acad. Sci. USA 102, 1649–1654 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Greer, E. L. et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J. Biol. Chem. 282, 30107–30119 (2007).
  Article CAS PubMed Google Scholar
• Lehtinen, M. K. et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125, 987–1001 (2006).
  Article CAS PubMed Google Scholar
• Huang, H., Regan, K. M., Lou, Z., Chen, J. & Tindall, D. J. CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science 314, 294–297 (2006).
  Article CAS PubMed Google Scholar
• Essers, M. A. et al. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J. 23, 4802–4812 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Ho, K. K. et al. Phosphorylation of FOXO3a on Ser-7 by p38 promotes its nuclear localization in response to doxorubicin. J. Biol. Chem. 287, 1545–1555 (2012).
  Article CAS PubMed Google Scholar
• Yamagata, K. et al. Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol. Cell 32, 221–231 (2008).
  Article CAS PubMed Google Scholar
• Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004). This article is the first to suggest that SIRT1 may differentially affect FOXO3A target gene expression.
  Article CAS PubMed Google Scholar
• Mihaylova, M. M. et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145, 607–621 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Khongkow, M. et al. SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer. Carcinogenesis 20 Mar 2013 (doi:10.1093/carcin/bgt098). A recent study showing that FOXO3A is targeted by SIRT6 in anticancer chemotherapeutic drug resistance.
• de Keizer, P. L. et al. Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence. Cancer Res. 70, 8526–8536 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Dijkers, P. F. et al. Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol. Cell. Biol. 20, 9138–9148 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Katayama, K., Nakamura, A., Sugimoto, Y., Tsuruo, T. & Fujita, N. FOXO transcription factor-dependent p15(INK4b) and p19(INK4d) expression. Oncogene 27, 1677–1686 (2008).
  Article CAS PubMed Google Scholar
• Medema, R. H., Kops, G. J., Bos, J. L. & Burgering, B. M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782–787 (2000).
  Article CAS PubMed Google Scholar
• Seoane, J., Le, H. V., Shen, L., Anderson, S. A. & Massague, J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117, 211–223 (2004).
  Article CAS PubMed Google Scholar
• Tran, H. et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 530–534 (2002).
  Article CAS PubMed Google Scholar
• Yuan, Z. et al. Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science 319, 1665–1668 (2008).
  Article CAS PubMed Google Scholar
• Fu, G. & Peng, C. Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells. Oncogene 30, 3953–3966 (2011).
  Article CAS PubMed Google Scholar
• Ciechomska, I., Pyrzynska, B., Kazmierczak, P. & Kaminska, B. Inhibition of Akt kinase signalling and activation of Forkhead are indispensable for upregulation of FasL expression in apoptosis of glioma cells. Oncogene 22, 7617–7627 (2003).
  Article CAS PubMed Google Scholar
• Essafi, A. et al. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene 24, 2317–2329 (2005).
  Article CAS PubMed Google Scholar
• Modur, V., Nagarajan, R., Evers, B. M. & Milbrandt, J. FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J. Biol. Chem. 277, 47928–47937 (2002).
  Article CAS PubMed Google Scholar
• Fernandez de Mattos, S. et al. FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism. Mol. Cell. Biol. 24, 10058–10071 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Lutzner, N., De-Castro Arce, J. & Rosl, F. Gene expression of the tumour suppressor LKB1 is mediated by Sp1, NF-Y and FOXO transcription factors. PLoS ONE 7, e32590 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Delpuech, O. et al. Induction of Mxi1-SR α by FOXO3a contributes to repression of Myc-dependent gene expression. Mol. Cell. Biol. 27, 4917–4930 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Bakker, W. J., Harris, I. S. & Mak, T. W. FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Mol. Cell 28, 941–953 (2007).
  Article CAS PubMed Google Scholar
• Storz, P., Doppler, H., Copland, J. A., Simpson, K. J. & Toker, A. FOXO3a promotes tumor cell invasion through the induction of matrix metalloproteinases. Mol. Cell. Biol. 29, 4906–4917 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Koo, C. Y., Muir, K. W. & Lam, E. W. FOXM1: from cancer initiation to progression and treatment. Biochim. Biophys. Acta 1819, 28–37 (2012).
  Article CAS PubMed Google Scholar
• Tan, Y., Raychaudhuri, P. & Costa, R. H. Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. Mol. Cell. Biol. 27, 1007–1016 (2007). This was the first report to link FOXM1 to DNA damage repair.
  Article CAS PubMed Google Scholar
• Zhang, N. et al. FoxM1 inhibition sensitizes resistant glioblastoma cells to temozolomide by downregulating the expression of DNA-repair gene Rad51. Clin. Cancer Res. 18, 5961–5971 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Monteiro, L. J. et al. The Forkhead Box M1 protein regulates BRIP1 expression and DNA damage repair in epirubicin treatment. Oncogene 29 Oct 2012 (doi:10.1038/onc.2012.491). This study reports a role of FOXM1 in DNA damage repair and genotoxic anticancer drug resistance.
• Kwok, J. M. et al. FOXM1 confers acquired cisplatin resistance in breast cancer cells. Mol. Cancer Res. 8, 24–34 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Millour, J. et al. ATM and p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance. Mol. Cancer Ther. 10, 1046–1058 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Balli, D., Zhang, Y., Snyder, J., Kalinichenko, V. V. & Kalin, T. V. Endothelial cell-specific deletion of transcription factor FoxM1 increases urethane-induced lung carcinogenesis. Cancer Res. 71, 40–50 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, I. M. et al. The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer. Cancer Res. 66, 2153–2161 (2006).
  Article CAS PubMed Google Scholar
• Wang, I. C. et al. Deletion of Forkhead Box M1 transcription factor from respiratory epithelial cells inhibits pulmonary tumorigenesis. PLoS ONE 4, e6609 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Yoshida, Y., Wang, I. C., Yoder, H. M., Davidson, N. O. & Costa, R. H. The forkhead box M1 transcription factor contributes to the development and growth of mouse colorectal cancer. Gastroenterology 132, 1420–1431 (2007).
  Article CAS PubMed Google Scholar
• Kalin, T. V. et al. Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice. Cancer Res. 66, 1712–1720 (2006). This was the first demonstration that FOXM1 has a role in tumorigenesis in a transgenic mouse model.
  Article CAS PubMed PubMed Central Google Scholar
• Barsotti, A. M. & Prives, C. Pro-proliferative FoxM1 is a target of p53-mediated repression. Oncogene 28, 4295–4305 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, I. C. et al. Foxm1 mediates cross talk between Kras/mitogen-activated protein kinase and canonical Wnt pathways during development of respiratory epithelium. Mol. Cell. Biol. 32, 3838–3850 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Sarrio, D. et al. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 68, 989–997 (2008).
  Article CAS PubMed Google Scholar
• Bao, B. et al. Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. J. Cell. Biochem. 112, 2296–2306 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, Z., Banerjee, S., Kong, D., Li, Y. & Sarkar, F. H. Down-regulation of Forkhead Box M1 transcription factor leads to the inhibition of invasion and angiogenesis of pancreatic cancer cells. Cancer Res. 67, 8293–8300 (2007).
  Article CAS PubMed Google Scholar
• Wang, I. C. et al. FoxM1 regulates transcription of JNK1 to promote the G1/S transition and tumor cell invasiveness. J. Biol. Chem. 283, 20770–20778 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Huang, C. et al. A novel FoxM1-caveolin signaling pathway promotes pancreatic cancer invasion and metastasis. Cancer Res. 72, 655–665 (2012).
  Article CAS PubMed Google Scholar
• Xie, Z. et al. Foxm1 transcription factor is required for maintenance of pluripotency of P19 embryonal carcinoma cells. Nucleic Acids Res. 38, 8027–8038 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Gemenetzidis, E. et al. Induction of human epithelial stem/progenitor expansion by FOXM1. Cancer Res. 70, 9515–9526 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, N. et al. FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell 20, 427–442 (2011). This paper describes the crosstalk between FOXM1 and WNT–β-catenin signalling in tumorigenesis.
  Article CAS PubMed PubMed Central Google Scholar
• Wang, Z. et al. FoxM1 in tumorigenicity of the neuroblastoma cells and renewal of the neural progenitors. Cancer Res. 71, 4292–4302 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Major, M. L., Lepe, R. & Costa, R. H. Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators. Mol. Cell. Biol. 24, 2649–2661 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Ma, R. Y. et al. Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c. J. Cell Sci. 118, 795–806 (2005).
  Article CAS PubMed Google Scholar
• Lee, C. S., Friedman, J. R., Fulmer, J. T. & Kaestner, K. H. The initiation of liver development is dependent on Foxa transcription factors. Nature 435, 944–947 (2005).
  Article CAS PubMed Google Scholar
• Bochkis, I. M. et al. Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress. Nature Med. 14, 828–836 (2008).
  Article CAS PubMed Google Scholar
• Li, Z., Tuteja, G., Schug, J. & Kaestner, K. H. Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell 148, 72–83 (2012). This detailed study describes the differential roles of FOXA proteins in females and males during hepatocarcinogenesis, in which FOXA proteins cooperate with ERα to suppress and AR to promote liver cancer in females and males, respectively.
  Article CAS PubMed PubMed Central Google Scholar
• Lin, L. et al. The hepatocyte nuclear factor 3 α gene, HNF3α (FOXA1), on chromosome band 14q13 is amplified and overexpressed in esophageal and lung adenocarcinomas. Cancer Res. 62, 5273–5279 (2002).
  CAS PubMed Google Scholar
• Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Robbins, C. M. et al. Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors. Genome Res. 21, 47–55 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012). References 74–76 conducted comprehensive surveys of mutations and amplifications of FOXA1 in prostate and breast cancer.
• DeGraff, D. J. et al. Loss of the urothelial differentiation marker FOXA1 is associated with high grade, late stage bladder cancer and increased tumor proliferation. PLoS ONE 7, e36669 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Barbieri, C. E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nature Genet. 44, 685–689 (2012).
  Article CAS PubMed Google Scholar
• Gao, N. et al. The role of hepatocyte nuclear factor-3 α (Forkhead Box A1) and androgen receptor in transcriptional regulation of prostatic genes. Mol. Endocrinol. 17, 1484–1507 (2003).
  Article CAS PubMed Google Scholar
• Zhang, L., Rubins, N. E., Ahima, R. S., Greenbaum, L. E. & Kaestner, K. H. Foxa2 integrates the transcriptional response of the hepatocyte to fasting. Cell. Metab. 2, 141–148 (2005).
  Article CAS PubMed Google Scholar
• Lupien, M. et al. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132, 958–970 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Clarke, C. L. & Graham, J. D. Non-overlapping progesterone receptor cistromes contribute to cell-specific transcriptional outcomes. PLoS ONE 7, e35859 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Robinson, J. L. & Carroll, J. S. FoxA1 is a key mediator of hormonal response in breast and prostate cancer. Front. Endocrinol. 3, 68 (2012).
  Article CAS Google Scholar
• Ross-Innes, C. S. et al. Cooperative interaction between retinoic acid receptor-α and estrogen receptor in breast cancer. Genes Dev. 24, 171–182 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Giatromanolaki, A. et al. Loss of expression and nuclear/cytoplasmic localization of the FOXP1 forkhead transcription factor are common events in early endometrial cancer: relationship with estrogen receptors and HIF-1α expression. Mod. Pathol. 19, 9–16 (2006).
  Article CAS PubMed Google Scholar
• Takayama, K. et al. FOXP1 is an androgen-responsive transcription factor that negatively regulates androgen receptor signaling in prostate cancer cells. Biochem. Biophys. Res. Commun. 374, 388–393 (2008).
  Article CAS PubMed Google Scholar
• Toma, M. I. et al. Expression of the Forkhead transcription factor FOXP1 is associated with tumor grade and Ki67 expression in clear cell renal cell carcinoma. Cancer Invest. 29, 123–129 (2011).
  Article PubMed Google Scholar
• Fox, S. B. et al. Expression of the forkhead transcription factor FOXP1 is associated with estrogen receptor α and improved survival in primary human breast carcinomas. Clin. Cancer Res. 10, 3521–3527 (2004).
  Article CAS PubMed Google Scholar
• Shigekawa, T. et al. FOXP1, an estrogen-inducible transcription factor, modulates cell proliferation in breast cancer cells and 5-year recurrence-free survival of patients with tamoxifen-treated breast cancer. Horm. Cancer 2, 286–297 (2011).
  Article CAS PubMed Google Scholar
• Feng, J. et al. High expression of FoxP1 is associated with improved survival in patients with non-small cell lung cancer. Am. J. Clin. Pathol. 138, 230–235 (2012).
  Article CAS PubMed Google Scholar
• Aster, J. & Kutok, J. Complexity Made simple in diffuse large B-cell lymphoma. Clin. Cancer Res. 15, 5291–5293 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, Y. X. et al. Prognostic significance of FOXP1 as an oncogene in hepatocellular carcinoma. J. Clin. Pathol. 65, 528–533 (2012).
  Article PubMed Google Scholar
• Hu, H. et al. Foxp1 is an essential transcriptional regulator of B cell development. Nature Immunol. 7, 819–826 (2006).
  Article CAS Google Scholar
• Ouyang, W. et al. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nature Immunol. 11, 618–627 (2010).
  Article CAS Google Scholar
• Liu, R. H. et al. FOXP3 up-regulates p21 expression by site-specific inhibition of histone deacetylase 2/histone deacetylase 4 association to the locus. Cancer Res. 69, 2252–2259 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Li, W. et al. Identification of a tumor suppressor relay between the FOXP3 and the Hippo pathways in breast and prostate cancers. Cancer Res. 71, 2162–2171 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, L. et al. Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell 16, 336–346 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Zuo, T. et al. FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 129, 1275–1286 (2007). This study was the first to demonstrate that FOXP3 is an X-linked breast cancer suppressor gene.
  Article CAS PubMed PubMed Central Google Scholar
• Zuo, T. et al. FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2. J. Clin. Invest. 117, 3765–3773 (2007).
  CAS PubMed PubMed Central Google Scholar
• Zhang, H. Y. & Sun, H. Up-regulation of Foxp3 inhibits cell proliferation, migration and invasion in epithelial ovarian cancer. Cancer Lett. 287, 91–97 (2010).
  Article CAS PubMed Google Scholar
• Whiteside, T. L. What are regulatory T cells (Treg) regulating in cancer and why? Semin. Cancer Biol. 22, 327–334 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Spiteri, E. et al. Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain. Am. J. Hum. Genet. 81, 1144–1157 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Campbell, A. J. et al. Aberrant expression of the neuronal transcription factor FOXP2 in neoplastic plasma cells. Br. J. Haematol. 149, 221–230 (2010).
  Article CAS PubMed Google Scholar
• Vernes, S. C. et al. High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders. Am. J. Hum. Genet. 81, 1232–1250 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Yasui, H., Hideshima, T., Richardson, P. G. & Anderson, K. C. Novel therapeutic strategies targeting growth factor signalling cascades in multiple myeloma. Br. J. Haematol. 132, 385–397 (2006).
  CAS PubMed Google Scholar
• Teufel, A., Wong, E. A., Mukhopadhyay, M., Malik, N. & Westphal, H. FoxP4, a novel forkhead transcription factor. Biochim. Et Biophys. Acta- 1627, 147–152 (2003).
  Article CAS Google Scholar
• Howarth, K. D. et al. Array painting reveals a high frequency of balanced translocations in breast cancer cell lines that break in cancer-relevant genes. Oncogene 27, 3345–3359 (2008).
  Article CAS PubMed Google Scholar
• Takata, R. et al. Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population. Nature Genet. 42, 751–754 (2010).
  Article CAS PubMed Google Scholar
• Rousso, D. L. et al. Foxp-mediated suppression of N-cadherin regulates neuroepithelial character and progenitor maintenance in the CNS. Neuron 74, 314–330 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Shu, W. et al. Foxp2 and Foxp1 cooperatively regulate lung and esophagus development. Development 134, 1991–2000 (2007).
  Article CAS PubMed Google Scholar
• Seo, S. & Kume, T. Forkhead transcription factors, Foxc1 and Foxc2, are required for the morphogenesis of the cardiac outflow tract. Dev. Biol. 296, 421–436 (2006).
  Article CAS PubMed Google Scholar
• Kume, T. The cooperative roles of Foxc1 and Foxc2 in cardiovascular development. Adv. Exp. Med. Biol. 665, 63–77 (2009).
  Article CAS PubMed Google Scholar
• Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008). This detailed study was the first to illustrate that FOXC proteins have a role in EMT and maintenance of stem cell properties.
  Article CAS PubMed PubMed Central Google Scholar
• Kong, D. et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS ONE 5, e12445 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Hollier, B. G. et al. FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer. Cancer Res. 73, 1981–1992 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Ray, P. S. et al. FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer. Cancer Res. 70, 3870–3876 (2010).
  Article CAS PubMed Google Scholar
• Taube, J. H. et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes Proc. Natl Acad. Sci. USA 107, 19132–19132 (2010).
  Article Google Scholar
• Wang, J. et al. FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling. Oncogene 31, 4798–4802 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Sizemore, S. T. & Keri, R. A. The forkhead box transcription factor FOXC1 promotes breast cancer invasion by inducing matrix metalloprotease 7 (MMP7) expression. J. Biol. Chem. 287, 24631–24640 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Xia, L. et al. Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. Hepatology 57, 610–624 (2013).
  Article CAS PubMed Google Scholar
• Hayashi, H., Sano, H., Seo, S. & Kume, T. The Foxc2 transcription factor regulates angiogenesis via induction of integrin β3 expression. J. Biol. Chem. 283, 23791–23800 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Sano, H. et al. The Foxc2 transcription factor regulates tumor angiogenesis. Biochem. Biophys. Res. Commun. 392, 201–206 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Mortazavi, F., An, J., Dubinett, S. & Rettig, M. p120-catenin is transcriptionally downregulated by FOXC2 in non-small cell lung cancer cells. Mol. Cancer Res. 8, 762–774 (2010).
  Article CAS PubMed Google Scholar
• Yusuf, D. et al. The transcription factor encyclopedia. Genome Biol. 13, R24 (2012). A comprehensive encyclopaedia of the FOX family and other transcription factors.
  Article PubMed PubMed Central Google Scholar
• Wang, F. et al. Synergistic interplay between promoter recognition and CBP/p300 coactivator recruitment by FOXO3a. ACS Chem. Biol. 4, 1017–1027 (2009).
  Article CAS PubMed Google Scholar
• Wang, F. et al. Structures of KIX domain of CBP in complex with two FOXO3a transactivation domains reveal promiscuity and plasticity in coactivator recruitment. Proc. Natl Acad. Sci. USA 109, 6078–6083 (2012).
  Article PubMed PubMed Central Google Scholar
• Carroll, J. S. et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122, 33–43 (2005). This study showed for the first time that ER binding at distal sites requires FOXA1 as a pioneer factor, revealing a potentially crucial role of FOXA1 deregulation in breast cancer progression.
  Article CAS PubMed Google Scholar
• Ross-Innes, C. S. et al. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature 481, 389–393 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Robinson, J. L. et al. Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1. EMBO J. 30, 3019–3027 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Serandour, A. A. et al. Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers. Genome Res. 21, 555–565 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Yan, J., Xu, L., Crawford, G., Wang, Z. & Burgess, S. M. The forkhead transcription factor FoxI1 remains bound to condensed mitotic chromosomes and stably remodels chromatin structure. Mol. Cell. Biol. 26, 155–168 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Strodicke, M., Karberg, S. & Korge, G. Domina (Dom), a new Drosophila member of the FKH/WH gene family, affects morphogenesis and is a suppressor of position-effect variegation. Mech. Dev. 96, 67–78 (2000).
  Article CAS PubMed Google Scholar
• Zaret, K. S., Caravaca, J. M., Tulin, A. & Sekiya, T. Nuclear mobility and mitotic chromosome binding: similarities between pioneer transcription factor FoxA and linker histone H1. Cold Spring Harb. Symp. Quant. Biol. 75, 219–226 (2010).
  Article CAS PubMed Google Scholar
• Li, Z. et al. Foxa2 and H2A.Z mediate nucleosome depletion during embryonic stem cell differentiation. Cell 151, 1608–1616 (2012). This detailed study describes the mechanism by which FOXA proteins alter chromatin structure and function as pioneer factors.
  Article CAS PubMed PubMed Central Google Scholar
• Hatta, M. & Cirillo, L. A. Chromatin opening and stable perturbation of core histone:DNA contacts by FoxO1. J. Biol. Chem. 282, 35583–35593 (2007).
  Article CAS PubMed Google Scholar
• Down, C. F., Millour, J., Lam, E. W. & Watson, R. J. Binding of FoxM1 to G2/M gene promoters is dependent upon B-Myb. Biochim. Biophys. Acta 1819, 855–862 (2012).
  Article CAS PubMed Google Scholar
• Sadasivam, S., Duan, S. & DeCaprio, J. A. The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression. Genes Dev. 26, 474–489 (2012). References 136 and 137 describe how BMYB and FOXM1 cooperate to regulate G2/M genes.
  Article CAS PubMed PubMed Central Google Scholar
• Cirillo, L. A. et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol. Cell 9, 279–289 (2002).
  Article CAS PubMed Google Scholar
• Bernardo, G. M. et al. FOXA1 is an essential determinant of ERα expression and mammary ductal morphogenesis. Development 137, 2045–2054 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kong, S. L., Li, G., Loh, S. L., Sung, W. K. & Liu, E. T. Cellular reprogramming by the conjoint action of ERα, FOXA1, and GATA3 to a ligand-inducible growth state. Mol. Syst. Biol. 7, 526 (2011). This article suggests a model for the coregulation of target genes by ERα, FOXA1 and GATA3.
  Article CAS PubMed PubMed Central Google Scholar
• Taslim, C. et al. Integrated analysis identifies a class of androgen-responsive genes regulated by short combinatorial long-range mechanism facilitated by CTCF. Nucleic Acids Res. 40, 4754–4764 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Potente, M. et al. Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J. Clin. Invest. 115, 2382–2392 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Baylin, S. B. & Ohm, J. E. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nature Rev. Cancer 6, 107–116 (2006).
  Article CAS Google Scholar
• Teh, M. T. et al. FOXM1 induces a global methylation signature that mimics the cancer epigenome in head and neck squamous cell carcinoma. PLoS ONE 7, e34329 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Carr, J. R. et al. FoxM1 regulates mammary luminal cell fate. Cell Rep. 1, 715–729 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Bettini, M. L. et al. Loss of epigenetic modification driven by the foxp3 transcription factor leads to regulatory T cell insufficiency. Immunity 36, 717–730 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Litvak, V. et al. A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature 490, 421–425 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Bidwell, B. N. et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nature Med. 18, 1224–1231 (2012).
  Article CAS PubMed Google Scholar
• Li, B. et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc. Natl Acad. Sci. USA 104, 4571–4576 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Tao, R. et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nature Med. 13, 1299–1307 (2007).
  Article CAS PubMed Google Scholar
• Kirkwood, J. M. & Tarhini, A. A. Biomarkers of therapeutic response in melanoma and renal cell carcinoma: potential inroads to improved immunotherapy. J. Clin. Oncol. 27, 2583–2585 (2009).
  Article CAS PubMed Google Scholar
• Jepsen, K., Gleiberman, A. S., Shi, C., Simon, D. I. & Rosenfeld, M. G. Cooperative regulation in development by SMRT and FOXP1. Genes Dev. 22, 740–745 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Chokas, A. L. et al. Foxp1/2/4-NuRD interactions regulate gene expression and epithelial injury response in the lung via regulation of interleukin-6. J. Biol. Chem. 285, 13304–13313 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Santisteban, P., Recacha, P., Metzger, D. E. & Zaret, K. S. Dynamic expression of Groucho-related genes Grg1 and Grg3 in foregut endoderm and antagonism of differentiation. Dev. Dyn. 239, 980–986 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Krol, J. et al. The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells. Mol. Cancer Ther. 6, 3169–3179 (2007).
  Article CAS PubMed Google Scholar
• Carr, J. R., Park, H. J., Wang, Z., Kiefer, M. M. & Raychaudhuri, P. FoxM1 mediates resistance to herceptin and paclitaxel. Cancer Res. 70, 5054–5063 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Hui, R. C. et al. The forkhead transcription factor FOXO3a increases phosphoinositide-3 kinase/Akt activity in drug-resistant leukemic cells through induction of PIK3CA expression. Mol. Cell. Biol. 28, 5886–5898 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Hui, R. C. et al. Doxorubicin activates FOXO3a to induce the expression of multidrug resistance gene ABCB1 (MDR1) in K562 leukemic cells. Mol. Cancer Ther. 7, 670–678 (2008).
  Article CAS PubMed Google Scholar
• de Olano, N. et al. The p38 MAPK-MK2 axis regulates E2F1 and FOXM1 expression after epirubicin treatment. Mol. Cancer Res, 10, 1189–1202 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Millour, J. et al. FOXM1 is a transcriptional target of ERα and has a critical role in breast cancer endocrine sensitivity and resistance. Oncogene 29, 2983–2995 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Madureira, P. A. et al. The Forkhead box M1 protein regulates the transcription of the estrogen receptor α in breast cancer cells. J. Biol. Chem. 281, 25167–25176 (2006).
  Article CAS PubMed Google Scholar
• Sanders, D. A., Ross-Innes, C. S., Beraldi, D., Carroll, J. S. & Balasubramanian, S. Genome-wide mapping of FOXM1 binding reveals co binding with estrogen receptor α in breast cancer cells. Genome Biol. 14, R6 (2013). This study reveals a new role of FOXM1 in the regulation of ER-target genes in breast cancer.
  Article PubMed PubMed Central Google Scholar
• Chen, J. et al. Constitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast cancer. PLoS ONE 5, e12293 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kwok, J. M. et al. Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression. Mol. Cancer Ther. 7, 2022–2032 (2008).
  Article CAS PubMed Google Scholar
• Myatt, S. S. & Lam, E. W. Targeting FOXM1. Nature Rev. Cancer 8, 242 (2008).
  Article CAS Google Scholar
• Wilson, M. S., Brosens, J. J., Schwenen, H. D. & Lam, E. W. FOXO and FOXM1 in cancer: the FOXO-FOXM1 axis shapes the outcome of cancer chemotherapy. Curr. Drug Targets 12, 1256–1266 (2011).
  Article CAS PubMed Google Scholar
• Hegde, N. S., Sanders, D. A., Rodriguez, R. & Balasubramanian, S. The transcription factor FOXM1 is a cellular target of the natural product thiostrepton. Nature Chem. 3, 725–731 (2011).
  Article CAS Google Scholar
• Kalinichenko, V. V. et al. Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev. 18, 830–850 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Gusarova, G. A. et al. A cell-penetrating ARF peptide inhibitor of FoxM1 in mouse hepatocellular carcinoma treatment. J. Clin. Invest. 117, 99–111 (2007).
  Article CAS PubMed Google Scholar
• Olmos, Y., Brosens, J. J. & Lam, E. W. Interplay between SIRT proteins and tumour suppressor transcription factors in chemotherapeutic resistance of cancer. Drug Resist. Updat. 14, 35–44 (2011).
  Article CAS PubMed Google Scholar
• Peck, B. et al. SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol. Cancer Ther. 9, 844–855 (2010).
  Article CAS PubMed Google Scholar
• Garrett, C. R. et al. Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT. Invest. New Drugs 29, 1381–1389 (2011).
  Article CAS PubMed Google Scholar
• Weigelt, B. & Downward, J. Genomic determinants of PI3K pathway inhibitor response in cancer. Front. Oncol. 2, 109 (2012).
  Article PubMed PubMed Central Google Scholar
• Britten, C. D. PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types. Cancer Chemother. Pharmacol. 27 Feb 2013 (doi:10.1007/s00280-013-2121-1).
• Zhang, X. et al. The tumor suppressive role of miRNA-370 by targeting FoxM1 in acute myeloid leukemia. Mol. Cancer 11, 56 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Chung, T. K. et al. Dysregulation of microRNA-204 mediates migration and invasion of endometrial cancer by regulating FOXC1. Int. J. Cancer 130, 1036–1045 (2012).
  Article CAS PubMed Google Scholar
• Priller, M. et al. Expression of FoxM1 is required for the proliferation of medulloblastoma cells and indicates worse survival of patients. Clin. Cancer Res. 17, 6791–6801 (2011).
  Article CAS PubMed Google Scholar
• Banham, A. H. et al. Expression of the forkhead transcription factor FOXP1 is associated both with hypoxia inducible factors (HIFs) and the androgen receptor in prostate cancer but is not directly regulated by androgens or hypoxia. Prostate 67, 1091–1098 (2007).
  Article CAS PubMed Google Scholar
• Myatt, S. S. et al. Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Cancer Res. 70, 367–377 (2010).
  Article CAS PubMed Google Scholar
• Teh, M. T. et al. Exploiting FOXM1-orchestrated molecular network for early squamous cell carcinoma diagnosis and prognosis. Int. J. Cancer 132, 2095–2106 (2013). This study describes one of the first attempts to use FOXM1 target gene signatures for reliable cancer diagnosis and prognosis.
  Article CAS PubMed Google Scholar
• Wang, F. et al. Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation. Oncogene 31, 1546–1557 (2012).
  Article CAS PubMed Google Scholar
• van der Heide, L. P. & Smidt, M. P. Regulation of FoxO activity by CBP/p300-mediated acetylation. Trends Biochem. Sci. 30, 81–86 (2005).
  Article CAS PubMed Google Scholar
• Chen, Y. J. et al. A conserved phosphorylation site within the forkhead domain of FoxM1B is required for its activation by cyclin-CDK1. J. Biol. Chem. 284, 30695–30707 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Wierstra, I. & Alves, J. Transcription factor FOXM1c is repressed by RB and activated by cyclin D1/Cdk4. Biol. Chem. 387, 949–962 (2006).
  CAS PubMed Google Scholar
• Laoukili, J. et al. Activation of FoxM1 during G2 requires cyclin A/Cdk-dependent relief of autorepression by the FoxM1 N-terminal domain. Mol. Cell. Biol. 28, 3076–3087 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Fu, Z. et al. Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression. Nature Cell Biol. 10, 1076–1082 (2008).
  Article CAS PubMed Google Scholar
• Anders, L. et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 20, 620–634 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Li, H. et al. Identification of tyrosine-phosphorylated proteins associated with metastasis and functional analysis of FER in human hepatocellular carcinoma cells. BMC Cancer 9, 366 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kohler, S. & Cirillo, L. A. Stable chromatin binding prevents FoxA acetylation, preserving FoxA chromatin remodeling. J. Biol. Chem. 285, 464–472 (2010).
  Article CAS PubMed Google Scholar
• Wang, Y. & Morrisey, E. Regulation of cardiomyocyte proliferation by Foxp1. Cell Cycle 9, 4251–4252 (2010).
  Article PubMed Google Scholar
• Danciu, T. E. et al. Small ubiquitin-like modifier (SUMO) modification mediates function of the inhibitory domains of developmental regulators FOXC1 and FOXC2. J. Biol. Chem. 287, 18318–18329 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Berry, F. B., Mirzayans, F. & Walter, M. A. Regulation of FOXC1 stability and transcriptional activity by an epidermal growth factor-activated mitogen-activated protein kinase signaling cascade. J. Biol. Chem. 281, 10098–10104 (2006).
  Article CAS PubMed Google Scholar
• Kwon, H. S. et al. Three novel acetylation sites in the Foxp3 transcription factor regulate the suppressive activity of regulatory T cells. J. Immunol. 188, 2712–2721 (2012).
  Article CAS PubMed Google Scholar
• Zhang, H., Xiao, Y., Zhu, Z., Li, B. & Greene, M. I. Immune regulation by histone deacetylases: a focus on the alteration of FOXP3 activity. Immunol. Cell Biol. 90, 95–100 (2012).
  Article CAS PubMed Google Scholar
• Vo, N. & Goodman, R. H. CREB-binding protein and p300 in transcriptional regulation. J. Biol. Chem. 276, 13505–13508 (2001).
  Article CAS PubMed Google Scholar
• Tan, S. K. et al. AP-2γ regulates oestrogen receptor-mediated long-range chromatin interaction and gene transcription. EMBO J. 30, 2569–2581 (2011).
  Article CAS PubMed PubMed Central Google Scholar