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Forkhead box proteins: tuning forks for transcriptional harmony

Nature Reviews Cancer volume 13, pages 482–495 (2013)Cite this article

Subjects

Key Points

  • Forkhead box (FOX) proteins are a superfamily of transcriptional regulators that have a key role both during development and in adult tissue homeostasis. Fifty human FOX proteins related through their 'forkhead' or 'winged-helix' DNA-binding domain (DBD) have been discovered, and they are further divided into 19 subfamilies (FOXA to FOXS) on the basis of sequence homology within and outside their forkhead domain.

  • Forkhead transcription factors, in particular FOXA, FOXC, FOXM, FOXO and FOXP proteins, are essential components of oncogenic and tumour suppressive pathways.

  • Deregulation of FOX proteins has a direct role in cancer initiation, maintenance, progression and drug resistance.

  • Control of various FOX family members is not only achieved through cell-specific expression, but is also fine-tuned by a myriad of post-translational modifications and through interactions with specific cofactors.

  • Besides being conventional transcriptional activators, FOX proteins also function as transcriptional repressors, pioneer factors, and they modulate and cooperate with other transcription factors and epigenetic effectors.

  • A better understanding of the mechanistic complexities that govern the regulation and functions of these FOX transcription factors should help us to realize their potential as therapeutic targets, as well as reliable predictive markers for cancer.

Abstract

Forkhead box (FOX) proteins are multifaceted transcription factors that are responsible for fine-tuning the spatial and temporal expression of a broad range of genes both during development and in adult tissues. This function is engrained in their ability to integrate a multitude of cellular and environmental signals and to act with remarkable fidelity. Several key members of the FOXA, FOXC, FOXM, FOXO and FOXP subfamilies are strongly implicated in cancer, driving initiation, maintenance, progression and drug resistance. The functional complexities of FOX proteins are coming to light and have established these transcription factors as possible therapeutic targets and putative biomarkers for specific cancers.

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Figure 1: Structural organization of the FOXO, FOXM, FOXA, FOXC and FOXP subfamilies.
Figure 2: Mechanisms of FOX-dependent transcriptional activation.
Figure 3: FOXO3A is a functional antagonist of FOXM1.
Figure 4: Models for FOX-dependent transcription repression.
Figure 5: Targeting the FOXO3A–FOXM1 axis in cancer therapeutics.

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References

  1. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  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). A recent survey of all human and mouse FOX genes.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 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 

  5. 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 

  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).

    CAS  PubMed  Google Scholar 

  7. 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 

  8. 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 

  9. Calnan, D. R. & Brunet, A. The FoxO code. Oncogene 27, 2276–2288 (2008).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. Hu, M. C. et al. IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117, 225–237 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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 

  26. 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 

  27. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). A recent study showing that FOXO3A is targeted by SIRT6 in anticancer chemotherapeutic drug resistance.

  30. 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 

  31. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  35. 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 

  36. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  39. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  41. 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 

  42. 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 

  43. 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 

  44. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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). This was the first report to link FOXM1 to DNA damage repair.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). This study reports a role of FOXM1 in DNA damage repair and genotoxic anticancer drug resistance.

  50. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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). This was the first demonstration that FOXM1 has a role in tumorigenesis in a transgenic mouse model.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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 

  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). This paper describes the crosstalk between FOXM1 and WNT–β-catenin signalling in tumorigenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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). 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 

  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).

    CAS  PubMed  Google Scholar 

  74. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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.

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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 

  79. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  81. 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 

  82. 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 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 HIF-1α expression. Mod. Pathol. 19, 9–16 (2006).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  89. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  91. 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 

  92. 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 

  93. Hu, H. et al. Foxp1 is an essential transcriptional regulator of B cell development. Nature Immunol. 7, 819–826 (2006).

    Article  CAS  Google Scholar 

  94. 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 

  95. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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 

  98. 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 

  99. 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 

  100. 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 

  101. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  109. 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 

  110. Shu, W. et al. Foxp2 and Foxp1 cooperatively regulate lung and esophagus development. Development 134, 1991–2000 (2007).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  112. 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 

  113. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  117. 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 

  118. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 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 

  123. 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 

  124. 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 

  125. 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 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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). 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 

  128. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  134. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  136. 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 

  137. 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 

  138. 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 

  139. 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 

  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). This article suggests a model for the coregulation of target genes by ERα, FOXA1 and GATA3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 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 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Carr, J. R. et al. FoxM1 regulates mammary luminal cell fate. Cell Rep. 1, 715–729 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  159. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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). This study reveals a new role of FOXM1 in the regulation of ER-target genes in breast cancer.

    Article  PubMed  PubMed Central  Google Scholar 

  163. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  165. Myatt, S. S. & Lam, E. W. Targeting FOXM1. Nature Rev. Cancer 8, 242 (2008).

    Article  CAS  Google Scholar 

  166. 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 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  173. Weigelt, B. & Downward, J. Genomic determinants of PI3K pathway inhibitor response in cancer. Front. Oncol. 2, 109 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  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/s00280-013-2121-1).

  175. 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 

  176. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  180. 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 

  181. 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 

  182. 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 

  183. 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 

  184. 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 

  185. 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 

  186. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. 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 

  190. Wang, Y. & Morrisey, E. Regulation of cardiomyocyte proliferation by Foxp1. Cell Cycle 9, 4251–4252 (2010).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  195. 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 

  196. 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 

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Acknowledgements

The work of E.W.-F.L. is supported by grants from Breast Cancer Campaign and Cancer Research UK. J.J.B. is supported by the Biomedical Research Unit in Reproductive Health, a joint initiative between the University Hospitals Coventry and Warwickshire NHS Trust and Warwick Medical School. A.R.G. is supported by Cancer Research UK and C.-Y.K. by Imperial College Healthcare NHS Trust.

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  1. Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK

    Eric W.-F. Lam, Ana R. Gomes & Chuay-Yeng Koo

  2. Division of Reproductive Health, Warwick Medical School, Clinical Sciences Research Laboratories, University Hospital, Coventry, CV2 2DX, UK

    Jan J. Brosens

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FOXO-dependent genes implicated in cancer initiation, progression or drug resistance (PDF 153 kb)

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FOXA-, FOXC-, FOXM- and FOXP-dependent genes implicated in cancer initiation, progression or drug resistance (PDF 157 kb)

Glossary

Pioneer factors

Transcription factors that can recognize specific DNA sequences and that actively open up compacted chromatin, rendering it competent for other factors to bind.

Spindle assembly checkpoint

A quality control mechanism that blocks chromosome segregation until all chromosomes are properly anchored to the microtubule spindle apparatus at kinetochores.

Homologous recombination

High-fidelity repair of DNA lesions, including double-strand breaks, in S and G2 phases of the cell cycle, using a sister chromatid as a template.

Sexual dimorphism

Difference in phenotype between males and females of the same species.

Cardiac outflow tract

Part of the heart through which blood passes in order to enter the great arteries.

Basal-like breast cancer

Subtype of aggressive breast cancer associated with poor prognosis that is high grade and triple-negative for the expression of oestrogen receptor, progesterone receptor and ERBB2.

BCR–ABL

A fusion protein that results from the reciprocal translocation between chromosome 9 and chromosome 22 (t(9;22)(q34;q11)) and is responsible for the induction of chronic myeloid leukaemia.

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Lam, EF., Brosens, J., Gomes, A. et al. Forkhead box proteins: tuning forks for transcriptional harmony. Nat Rev Cancer 13, 482–495 (2013). https://doi.org/10.1038/nrc3539

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