Forkhead box proteins: Tuning forks for transcriptional harmony

Nature Reviews Cancer

Volumn 13, Issue 7, 2013, Pages 482-495

  Lam, Eric W F ^a   Brosens, Jan J ^b   Gomes, Ana R ^a   Koo, Chuay Yeng ^a  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY OF WARWICK   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

4 DIALLYLAMINOMETHYLENE 1,3,4,7,10,11,12,13,14,15,16,17 DODECAHYDRO 6 HYDROXY 1 METHOXYMETHYL 10,13 DIMETHYL 3,7,17 TRIOXO 2 OXACYCLOPENTA[A]PHENANTHREN 11 YL ACETATE; ANTINEOPLASTIC AGENT; BAY 869766; BIOLOGICAL MARKER; BUPARLISIB; CARRIER PROTEINS AND BINDING PROTEINS; CISPLATIN; COBIMETINIB; COLLAGENASE 3; DOXORUBICIN; EPIRUBICIN; EX 527; FORKHEAD TRANSCRIPTION FACTOR; GEFITINIB; GELATINASE B; HEPATOCYTE NUCLEAR FACTOR 3ALPHA; HEPATOCYTE NUCLEAR FACTOR 3BETA; HEPATOCYTE NUCLEAR FACTOR 3GAMMA; HYPOXIA INDUCIBLE FACTOR 1ALPHA; IMATINIB; LAPATINIB; NUCLEIC ACID BINDING PROTEIN; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR FKHR; TRANSCRIPTION FACTOR FKHRL1; TRANSCRIPTION FACTOR FOXC1; TRANSCRIPTION FACTOR FOXC2; TRANSCRIPTION FACTOR FOXM1; TRANSCRIPTION FACTOR FOXO; TRANSCRIPTION FACTOR FOXO4; TRANSCRIPTION FACTOR FOXP1; TRASTUZUMAB; TUMOR SUPPRESSOR PROTEIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASCULOTROPIN; XL 147;

ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER CELL; CANCER CHEMOTHERAPY; CANCER RESISTANCE; CARCINOGENESIS; CELL CYCLE; CELL CYCLE PROGRESSION; CELL DIFFERENTIATION; CELL INVASION; CELL METABOLISM; CELL MIGRATION; CELL PROLIFERATION; CELL RENEWAL; CYTOTOXICITY; GENE EXPRESSION; GENE OVEREXPRESSION; GENE REPRESSION; HUMAN; MOLECULARLY TARGETED THERAPY; NEOPLASM; OXIDATIVE STRESS; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN FUNCTION; PROTEIN TARGETING; RECEPTOR DOWN REGULATION; RECEPTOR UPREGULATION; REVIEW; SIGNAL TRANSDUCTION; STEM CELL; TRANSCRIPTION INITIATION; TRANSCRIPTOMICS; TUMOR SUPPRESSOR GENE; TUNING FORK;

ANTINEOPLASTIC AGENTS; FORKHEAD TRANSCRIPTION FACTORS; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASMS;

EID: 84881107561     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3539     Document Type: Review

References (196)

1. Myatt, S. S. & Lam, E. W. The emerging roles of forkhead box (Fox) proteins in cancer. Nature Rev. Cancer 7, 847-859 (2007).
2. 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).
3. 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).
4. Kaestner, K. H., Knochel, W. & Martinez, D. E. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev. 14, 142-146 (2000).
5. McGovern, U. B. et al. Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer. Mol. Cancer Ther. 8, 582-591 (2009).
6. 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).
7. Karadedou, C. T. et al. FOXO3a represses VEGF expression through FOXM1dependent and-independent mechanisms in breast cancer. Oncogene 31, 1845-1858 (2012).
8. Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: Establishing competence for gene expression. Genes Dev. 25, 2227-2241 (2011).
9. Calnan, D. R. & Brunet, A. The FoxO code. Oncogene 27, 2276-2288 (2008).
10. 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).
11. 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).
12. 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).
13. 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).
14. Paik, J. H. et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309-323 (2007).
15. 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).
16. Yang, J. Y. et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2mediated degradation. Nature Cell Biol. 10, 138-148 (2008).
17. Hu, M. C. et al. IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117, 225-237 (2004).
18. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868 (1999).
19. 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).
20. Huang, H. et al. Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc. Natl Acad. Sci. USA 102, 1649-1654 (2005).
21. 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).
22. Lehtinen, M. K. et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125, 987-1001 (2006).
23. Huang, H., Regan, K. M., Lou, Z., Chen, J. & Tindall, D. J. CDK2dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science 314, 294-297 (2006).
24. 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).
25. Ho, K. K. et al. Phosphorylation of FOXO3a on Ser7 by p38 promotes its nuclear localization in response to doxorubicin. J. Biol. Chem. 287, 1545-1555 (2012).
26. Yamagata, K. et al. Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol. Cell 32, 221-231 (2008).
27. Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011-2015 (2004).
28. Mihaylova, M. M. et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145, 607-621 (2011).
29. Khongkow, M. et al. SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer. Carcinogenesis 20 Mar 2013 (doi:10.1093/carcin/ bgt098).
30. de Keizer, P. L. et al. Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1dependent senescence. Cancer Res. 70, 8526-8536 (2010).
31. Dijkers, P. F. et al. Forkhead transcription factor FKHRL1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol. Cell. Biol. 20, 9138-9148 (2000).
32. 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).
33. 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).
34. 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).
35. Tran, H. et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 530-534 (2002).
36. Yuan, Z. et al. Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science 319, 1665-1668 (2008).
37. 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).
38. 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).
39. Essafi, A. et al. Direct transcriptional regulation of Bim by FoxO3a mediates STI571induced apoptosis in Bcr-Abl-expressing cells. Oncogene 24, 2317-2329 (2005).
40. 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).
41. Fernandez de Mattos, S. et al. FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6dependent mechanism. Mol. Cell. Biol. 24, 10058-10071 (2004).
42. Lutzner, N., DeCastro Arce, J. & Rosl, F. Gene expression of the tumour suppressor LKB1 is mediated by Sp1, NFY and FOXO transcription factors. PLoS ONE 7, e32590 (2012).
43. Delpuech, O. et al. Induction of Mxi1SR α by FOXO3a contributes to repression of Myc-dependent gene expression. Mol. Cell. Biol. 27, 4917-4930 (2007).
44. Bakker, W. J., Harris, I. S. & Mak, T. W. FOXO3a is activated in response to hypoxic stress and inhibits HIF1induced apoptosis via regulation of CITED2. Mol. Cell 28, 941-953 (2007).
45. 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).
46. Koo, C. Y., Muir, K. W. & Lam, E. W. FOXM1: From cancer initiation to progression and treatment. Biochim. Biophys. Acta 1819, 28-37 (2012).
47. 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).
48. 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).
49. 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).
50. Kwok, J. M. et al. FOXM1 confers acquired cisplatin resistance in breast cancer cells. Mol. Cancer Res. 8, 24-34 (2010).
51. 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).
52. 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).
53. 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).
54. Wang, I. C. et al. Deletion of Forkhead Box M1 transcription factor from respiratory epithelial cells inhibits pulmonary tumorigenesis. PLoS ONE 4, e6609 (2009).
55. 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).
56. 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).
57. Barsotti, A. M. & Prives, C. Pro-proliferative FoxM1 is a target of p53mediated repression. Oncogene 28, 4295-4305 (2009).
58. 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).
59. Sarrio, D. et al. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 68, 989-997 (2008).
60. 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).
61. 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).
62. 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).
63. Huang, C. et al. A novel FoxM1caveolin signaling pathway promotes pancreatic cancer invasion and metastasis. Cancer Res. 72, 655-665 (2012).
64. 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).
65. Gemenetzidis, E. et al. Induction of human epithelial stem/progenitor expansion by FOXM1. Cancer Res. 70, 9515-9526 (2010).
66. 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).
67. Wang, Z. et al. FoxM1 in tumorigenicity of the neuroblastoma cells and renewal of the neural progenitors. Cancer Res. 71, 4292-4302 (2011).
68. 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).
69. 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).
70. 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).
71. 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).
72. 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).
73. 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).
74. Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239-243 (2012).
75. 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).
76. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70 (2012).
77. 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).
78. Barbieri, C. E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nature Genet. 44, 685-689 (2012).
79. Gao, N. et al. The role of hepatocyte nuclear factor3 α (Forkhead Box A1) and androgen receptor in transcriptional regulation of prostatic genes. Mol. Endocrinol. 17, 1484-1507 (2003).
80. 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).
81. Lupien, M. et al. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132, 958-970 (2008).
82. Clarke, C. L. & Graham, J. D. Non-overlapping progesterone receptor cistromes contribute to cell-specific transcriptional outcomes. PLoS ONE 7, e35859 (2012).
83. Robinson, J. L. & Carroll, J. S. FoxA1 is a key mediator of hormonal response in breast and prostate cancer. Front. Endocrinol. 3, 68 (2012).
84. 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).
85. 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 HIF1α expression. Mod. Pathol. 19, 9-16 (2006).
86. 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).
87. 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).
88. 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).
89. Shigekawa, T. et al. FOXP1, an estrogen-inducible transcription factor, modulates cell proliferation in breast cancer cells and 5year recurrence-free survival of patients with tamoxifen-treated breast cancer. Horm. Cancer 2, 286-297 (2011).
90. 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).
91. Aster, J. & Kutok, J. Complexity Made simple in diffuse large Bcell lymphoma. Clin. Cancer Res. 15, 5291-5293 (2009).
92. Zhang, Y. X. et al. Prognostic significance of FOXP1 as an oncogene in hepatocellular carcinoma. J. Clin. Pathol. 65, 528-533 (2012).
93. Hu, H. et al. Foxp1 is an essential transcriptional regulator of B cell development. Nature Immunol. 7, 819-826 (2006).
94. Ouyang, W. et al. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nature Immunol. 11, 618-627 (2010).
95. Liu, R. H. et al. FOXP3 upregulates p21 expression by site-specific inhibition of histone deacetylase 2/histone deacetylase 4 association to the locus. Cancer Res. 69, 2252-2259 (2009).
96. 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).
97. Wang, L. et al. Somatic single hits inactivate the Xlinked tumor suppressor FOXP3 in the prostate. Cancer Cell 16, 336-346 (2009).
98. Zuo, T. et al. FOXP3 is an Xlinked breast cancer suppressor gene and an important repressor of the HER2/ErbB2 oncogene. Cell 129, 1275-1286 (2007).
99. Zuo, T. et al. FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2. J. Clin. Invest. 117, 3765-3773 (2007).
100. Zhang, H. Y. & Sun, H. Upregulation of Foxp3 inhibits cell proliferation, migration and invasion in epithelial ovarian cancer. Cancer Lett. 287, 91-97 (2010).
101. Whiteside, T. L. What are regulatory T cells (Treg) regulating in cancer and why? Semin. Cancer Biol. 22, 327-334 (2012).
102. 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).
103. Campbell, A. J. et al. Aberrant expression of the neuronal transcription factor FOXP2 in neoplastic plasma cells. Br. J. Haematol. 149, 221-230 (2010).
104. 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).
105. 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).
106. 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).
107. 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).
108. 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).
109. Rousso, D. L. et al. Foxp-mediated suppression of Ncadherin regulates neuroepithelial character and progenitor maintenance in the CNS. Neuron 74, 314-330 (2012).
110. Shu, W. et al. Foxp2 and Foxp1 cooperatively regulate lung and esophagus development. Development 134, 1991-2000 (2007).
111. 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).
112. Kume, T. The cooperative roles of Foxc1 and Foxc2 in cardiovascular development. Adv. Exp. Med. Biol. 665, 63-77 (2009).
113. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704-715 (2008).
114. Kong, D. et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS ONE 5, e12445 (2010).
115. Hollier, B. G. et al. FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer. Cancer Res. 73, 1981-1992 (2013).
116. 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).
117. Taube, J. H. et al. Core epithelial-tomesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes Proc. Natl Acad. Sci. USA 107, 19132-19132 (2010).
118. Wang, J. et al. FOXC1 regulates the functions of human basal-like breast cancer cells by activating NFκB signaling. Oncogene 31, 4798-4802 (2012).
119. 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).
120. Xia, L. et al. Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. Hepatology 57, 610-624 (2013).
121. 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).
122. Sano, H. et al. The Foxc2 transcription factor regulates tumor angiogenesis. Biochem. Biophys. Res. Commun. 392, 201-206 (2010).
123. Mortazavi, F., An, J., Dubinett, S. & Rettig, M. p120catenin is transcriptionally downregulated by FOXC2 in non-small cell lung cancer cells. Mol. Cancer Res. 8, 762-774 (2010).
124. Yusuf, D. et al. The transcription factor encyclopedia. Genome Biol. 13, R24 (2012).
125. Wang, F. et al. Synergistic interplay between promoter recognition and CBP/p300 coactivator recruitment by FOXO3a. ACS Chem. Biol. 4, 1017-1027 (2009).
126. 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).
127. 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).
128. Ross-Innes, C. S. et al. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature 481, 389-393 (2012).
129. Robinson, J. L. et al. Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1. EMBO J. 30, 3019-3027 (2011).
130. Serandour, A. A. et al. Epigenetic switch involved in activation of pioneer factor FOXA1dependent enhancers. Genome Res. 21, 555-565 (2011).
131. 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).
132. 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).
133. 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).
134. Li, Z. et al. Foxa2 and H2A.Z mediate nucleosome depletion during embryonic stem cell differentiation. Cell 151, 1608-1616 (2012).
135. Hatta, M. & Cirillo, L. A. Chromatin opening and stable perturbation of core histone:DNA contacts by FoxO1. J. Biol. Chem. 282, 35583-35593 (2007).
136. Down, C. F., Millour, J., Lam, E. W. & Watson, R. J. Binding of FoxM1 to G2/M gene promoters is dependent upon BMyb. Biochim. Biophys. Acta 1819, 855-862 (2012).
137. Sadasivam, S., Duan, S. & DeCaprio, J. A. The MuvB complex sequentially recruits BMyb and FoxM1 to promote mitotic gene expression. Genes Dev. 26, 474-489 (2012).
138. Cirillo, L. A. et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA4. Mol. Cell 9, 279-289 (2002).
139. Bernardo, G. M. et al. FOXA1 is an essential determinant of ERα expression and mammary ductal morphogenesis. Development 137, 2045-2054 (2010).
140. 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).
141. 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).
142. Potente, M. et al. Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J. Clin. Invest. 115, 2382-2392 (2005).
143. 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).
144. 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).
145. Carr, J. R. et al. FoxM1 regulates mammary luminal cell fate. Cell Rep. 1, 715-729 (2012).
146. 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).
147. Litvak, V. et al. A FOXO3IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature 490, 421-425 (2012).
148. 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).
149. 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).
150. Tao, R. et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nature Med. 13, 1299-1307 (2007).
151. 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).
152. 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).
153. Chokas, A. L. et al. Foxp1/2/4NuRD interactions regulate gene expression and epithelial injury response in the lung via regulation of interleukin6. J. Biol. Chem. 285, 13304-13313 (2010).
154. 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).
155. 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).
156. 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).
157. Hui, R. C. et al. The forkhead transcription factor FOXO3a increases phosphoinositide3 kinase/Akt activity in drug-resistant leukemic cells through induction of PIK3CA expression. Mol. Cell. Biol. 28, 5886-5898 (2008).
158. 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).
159. de Olano, N. et al. The p38 MAPKMK2 axis regulates E2F1 and FOXM1 expression after epirubicin treatment. Mol. Cancer Res, 10, 1189-1202 (2012).
160. 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).
161. 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).
162. 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).
163. Chen, J. et al. Constitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast cancer. PLoS ONE 5, e12293 (2010).
164. 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).
165. Myatt, S. S. & Lam, E. W. Targeting FOXM1. Nature Rev. Cancer 8, 242 (2008).
166. Wilson, M. S., Brosens, J. J., Schwenen, H. D. & Lam, E. W. FOXO and FOXM1 in cancer: The FOXOFOXM1 axis shapes the outcome of cancer chemotherapy. Curr. Drug Targets 12, 1256-1266 (2011).
167. 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).
168. 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).
169. 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).
170. 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).
171. 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).
172. 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).
173. Weigelt, B. & Downward, J. Genomic determinants of PI3K pathway inhibitor response in cancer. Front. Oncol. 2, 109 (2012).
174. Britten, C. D. PI3K and MEK inhibitor combinations: Examining the evidence in selected tumor types. Cancer Chemother. Pharmacol. 27 Feb 2013 (doi:10.1007/s0028001321211).
175. Zhang, X. et al. The tumor suppressive role of miRNA370 by targeting FoxM1 in acute myeloid leukemia. Mol. Cancer 11, 56 (2012).
176. Chung, T. K. et al. Dysregulation of microRNA204 mediates migration and invasion of endometrial cancer by regulating FOXC1. Int. J. Cancer 130, 1036-1045 (2012).
177. 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).
178. 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).
179. 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).
180. Teh, M. T. et al. Exploiting FOXM1orchestrated molecular network for early squamous cell carcinoma diagnosis and prognosis. Int. J. Cancer 132, 2095-2106 (2013).
181. Wang, F. et al. Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2mediated FOXO3 ubiquitination and degradation. Oncogene 31, 1546-1557 (2012).
182. van der Heide, L. P. & Smidt, M. P. Regulation of FoxO activity by CBP/p300mediated acetylation. Trends Biochem. Sci. 30, 81-86 (2005).
183. Chen, Y. J. et al. A conserved phosphorylation site within the forkhead domain of FoxM1B is required for its activation by cyclinCDK1. J. Biol. Chem. 284, 30695-30707 (2009).
184. Wierstra, I. & Alves, J. Transcription factor FOXM1c is repressed by RB and activated by cyclin D1/Cdk4. Biol. Chem. 387, 949-962 (2006).
185. Laoukili, J. et al. Activation of FoxM1 during G2 requires cyclin A/Cdk-dependent relief of autorepression by the FoxM1 Nterminal domain. Mol. Cell. Biol. 28, 3076-3087 (2008).
186. Fu, Z. et al. Plk1dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression. Nature Cell Biol. 10, 1076-1082 (2008).
187. 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).
188. 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).
189. Kohler, S. & Cirillo, L. A. Stable chromatin binding prevents FoxA acetylation, preserving FoxA chromatin remodeling. J. Biol. Chem. 285, 464-472 (2010).
190. Wang, Y. & Morrisey, E. Regulation of cardiomyocyte proliferation by Foxp1. Cell Cycle 9, 4251-4252 (2010).
191. 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).
192. 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).
193. 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).
194. 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).
195. Vo, N. & Goodman, R. H. CREB-binding protein and p300 in transcriptional regulation. J. Biol. Chem. 276, 13505-13508 (2001).
196. Tan, S. K. et al. AP2γ regulates oestrogen receptor-mediated long-range chromatin interaction and gene transcription. EMBO J. 30, 2569-2581 (2011).