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Forkhead transcription factor FOXF1 is a novel target gene of the p53 family and regulates cancer cell migration and invasiveness

Abstract

p53 is an established tumor suppressor that can activate the transcription of multiple target genes. Recent evidence suggests that p53 may contribute to the regulation of cell invasion and migration. In this study, we show that the forkhead box transcription factor FOXF1 is a novel target of the p53 family because FOXF1 is upregulated by p53, TAp73 and TAp63. We show that FOXF1 is induced upon DNA damage in a p53-dependent manner. Furthermore, we identified a response element located within the FOXF1 gene that is responsive to wild-type p53, TAp73β and TAp63γ. The ectopic expression of FOXF1 inhibited cancer cell invasion and migration, whereas the inactivation of FOXF1 stimulated cell invasion and migration. We also show that FOXF1 regulates the transcriptional activity of E-cadherin (CDH1) by acting on its FOXF1 consensus binding site located upstream of the E-cadherin gene. Collectively, our results show that FOXF1 is a p53 family target gene, and our data suggest that FOXF1 and p53 form a portion of a regulatory transcriptional network that appears to have an important role in cancer cell invasion and migration.

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References

  1. Vogelstein B, Lane D, Levine AJ . Surfing the p53 network. Nature 2000; 408: 307–310.

    Article  CAS  PubMed  Google Scholar 

  2. el-Deiry WS . Regulation of p53 downstream genes. Semin Cancer Biol 1998; 8: 345–357.

    Article  CAS  PubMed  Google Scholar 

  3. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75: 817–825.

    Article  CAS  PubMed  Google Scholar 

  4. Tokino T, Nakamura Y . The role of p53-target genes in human cancer. Crit Rev Oncol Hematol 2000; 33: 1–6.

    Article  CAS  PubMed  Google Scholar 

  5. Zou Z, Gao C, Nagaich AK, Connell T, Saito S, Moul JW et al. p53 regulates the expression of the tumor suppressor gene maspin. J Biol Chem 2000; 275: 6051–6054.

    Article  CAS  PubMed  Google Scholar 

  6. Arachchige Don AS, Dallapiazza RF, Bennin DA, Brake T, Cowan CE, Horne MC . Cyclin G2 is a centrosome-associated nucleocytoplasmic shuttling protein that influences microtubule stability and induces a p53-dependent cell cycle arrest. Exp Cell Res 2006; 312: 4181–4204.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Liu JJ, Chung TK, Li J, Taneja R . Sharp-1 modulates the cellular response to DNA damage. FEBS Lett 2010; 584: 619–624.

    Article  CAS  PubMed  Google Scholar 

  8. Hsiao BY, Chen CC, Hsieh PC, Chang TK, Yeh YC, Wu YC et al. Rad is a p53 direct transcriptional target that inhibits cell migration and is frequently silenced in lung carcinoma cells. J Mol Med (Berl) 2011; 89: 481–492.

    Article  CAS  Google Scholar 

  9. Hwang CI, Choi J, Zhou Z, Flesken-Nikitin A, Tarakhovsky A, Nikitin AY . MET-dependent cancer invasion may be preprogrammed by early alterations of p53-regulated feedforward loop and triggered by stromal cell-derived HGF. Cell Cycle 2011; 10: 3834–3840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jost CA, Marin MC, Kaelin WG Jr. . p73 is a simian p53-related protein that can induce apoptosis. Nature 1997; 389: 191–194.

    Article  CAS  PubMed  Google Scholar 

  11. Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 1997; 90: 809–819.

    Article  CAS  PubMed  Google Scholar 

  12. Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 1998; 2: 305–316.

    Article  CAS  PubMed  Google Scholar 

  13. Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 1999; 398: 714–718.

    Article  CAS  PubMed  Google Scholar 

  14. Irwin MS, Kaelin WG . p53 family update: p73 and p63 develop their own identities. Cell Growth Differ 2001; 12: 337–349.

    CAS  PubMed  Google Scholar 

  15. Yang A, Kaghad M, Caput D, McKeon F . On the shoulders of giants: p63, p73 and the rise of p53. Trends Genet 2002; 18: 90–95.

    Article  PubMed  Google Scholar 

  16. Yang A, McKeon F . P63 and P73: P53 mimics, menaces and more. Nat Rev Mol Cell Biol 2001; 1: 199–207.

    Article  Google Scholar 

  17. Harms KL, Chen X . The functional domains in p53 family proteins exhibit both common and distinct properties. Cell Death Differ 2006; 13: 890–897.

    Article  CAS  PubMed  Google Scholar 

  18. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011; 333: 1157–1160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lu C, Wang W, El-Deiry WS . Non-genotoxic anti-neoplastic effects of ellipticine derivative NSC176327 in p53-deficient human colon carcinoma cells involve stimulation of p73. Cancer Biol Ther 2008; 7: 2039–2046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen F, Wang W, El-Deiry WS . Current strategies to target p53 in cancer. Biochem Pharmacol 2010; 80: 724–730.

    Article  CAS  PubMed  Google Scholar 

  21. Lo PK, Lee JS, Liang X, Han L, Mori T, Fackler MJ et al. Epigenetic inactivation of the potential tumor suppressor gene FOXF1 in breast cancer. Cancer Res 2010; 70: 6047–6058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lo PK, Lee JS, Sukumar S . The p53-p21WAF1 checkpoint pathway plays a protective role in preventing DNA rereplication induced by abrogation of FOXF1 function. Cell Signal 2012; 24: 316–324.

    Article  CAS  PubMed  Google Scholar 

  23. Watson JE, Doggett NA, Albertson DG, Andaya A, Chinnaiyan A, van Dekken H et al. Integration of high-resolution array comparative genomic hybridization analysis of chromosome 16q with expression array data refines common regions of loss at 16q23-qter and identifies underlying candidate tumor suppressor genes in prostate cancer. Oncogene 2004; 23: 3487–3494.

    Article  CAS  PubMed  Google Scholar 

  24. Ishida S, Yamashita T, Nakaya U, Tokino T . Adenovirus-mediated transfer of p53-related genes induces apoptosis of human cancer cells. Jpn J Cancer Res 2000; 91: 174–180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sasaki Y, Mita H, Toyota M, Ishida S, Morimoto I, Yamashita T et al. Identification of the interleukin 4 receptor alpha gene as a direct target for p73. Cancer Res 2003; 63: 8145–8152.

    CAS  PubMed  Google Scholar 

  26. Sasaki Y, Naishiro Y, Oshima Y, Imai K, Nakamura Y, Tokino T . Identification of pigment epithelium-derived factor as a direct target of the p53 family member genes. Oncogene 2005; 24: 5131–5136.

    Article  CAS  PubMed  Google Scholar 

  27. Sasaki Y, Oshima Y, Koyama R, Maruyama R, Akashi H, Mita H et al. Identification of flotillin-2, a major protein on lipid rafts, as a novel target of p53 family members. Mol Cancer Res 2008; 6: 395–406.

    Article  CAS  PubMed  Google Scholar 

  28. Fomenkov A, Zangen R, Huang YP, Osada M, Guo Z, Fomenkov T et al. RACK1 and stratifin target DeltaNp63alpha for a proteasome degradation in head and neck squamous cell carcinoma cells upon DNA damage. Cell Cycle 2004; 3: 1285–1295.

    Article  CAS  PubMed  Google Scholar 

  29. Liefer KM, Koster MI, Wang XJ, Yang A, McKeon F, Roop DR . Down-regulation of p63 is required for epidermal UV-B-induced apoptosis. Cancer Res 2000; 60: 4016–4020.

    CAS  PubMed  Google Scholar 

  30. Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG . FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res 2002; 62: 4773–4780.

    CAS  PubMed  Google Scholar 

  31. Shiota M, Song Y, Yokomizo A, Kiyoshima K, Tada Y, Uchino H et al. Foxo3a suppression of urothelial cancer invasiveness through Twist1, Y-box-binding protein 1, and E-cadherin regulation. Clin Cancer Res 2010; 16: 5654–5663.

    Article  CAS  PubMed  Google Scholar 

  32. Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 2007; 9: 166–180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mizuno H, Kitada K, Nakai K, Sarai A . PrognoScan: a new database for meta-analysis of the prognostic value of genes. BMC Med Genomics 2009; 2: 18.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Pierrou S, Hellqvist M, Samuelsson L, Enerback S, Carlsson P . Cloning and characterization of seven human forkhead proteins: binding site specificity and DNA bending. EMBO J 1994; 13: 5002–5012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lomenick JP, Hubert MA, Handwerger S . Transcription factor FOXF1 regulates growth hormone variant gene expression. Am J Physiol Endocrinol Metab 2006; 291: E947–E951.

    Article  CAS  PubMed  Google Scholar 

  36. Sasaki Y, Negishi H, Idogawa M, Yokota I, Koyama R, Kusano M et al. p53 negatively regulates the hepatoma growth factor HDGF. Cancer Res 2011; 71: 7038–7047.

    Article  CAS  PubMed  Google Scholar 

  37. Barbieri CE, Tang LJ, Brown KA, Pietenpol JA . Loss of p63 leads to increased cell migration and up-regulation of genes involved in invasion and metastasis. Cancer Res 2006; 66: 7589–7597.

    Article  CAS  PubMed  Google Scholar 

  38. Graziano V, De Laurenzi V . Role of p63 in cancer development. Biochim Biophys Acta 2011; 1816: 57–66.

    CAS  PubMed  Google Scholar 

  39. Melino G . p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53. Cell Death Differ 2011; 18: 1487–1499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Stiewe T . The p53 family in differentiation and tumorigenesis. Nat Rev Cancer 2007; 7: 165–168.

    Article  CAS  PubMed  Google Scholar 

  41. Su X, Chakravarti D, Flores ER . p63 steps into the limelight: crucial roles in the suppression of tumorigenesis and metastasis. Nat Rev Cancer 2012; 13: 136–143.

    Article  Google Scholar 

  42. Tucci P, Agostini M, Grespi F, Markert EK, Terrinoni A, Vousden KH et al. Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer. Proc Natl Acad Sci USA 2012; 109: 15312–15317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wu N, Rollin J, Masse I, Lamartine J, Gidrol X . p63 regulates human keratinocyte proliferation via MYC-regulated gene network and differentiation commitment through cell adhesion-related gene network. J Biol Chem 2012; 287: 5627–5638.

    Article  CAS  PubMed  Google Scholar 

  44. Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 2010; 467: 986–990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Adorno M, Cordenonsi M, Montagner M, Dupont S, Wong C, Hann B et al. A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell 2009; 137: 87–98.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang Y, Yan W, Jung YS, Chen X . Mammary epithelial cell polarity is regulated differentially by p73 isoforms via epithelial-to-mesenchymal transition. J Biol Chem 2012; 287: 17746–17753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cavallaro U, Christofori G . Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 2004; 4: 118–132.

    Article  CAS  PubMed  Google Scholar 

  48. Pecina-Slaus N . Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Cancer Cell Int 2003; 3: 17.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Berx G, Cleton-Jansen AM, Nollet F, de Leeuw WJ, van de Vijver M, Cornelisse C et al. E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J 1995; 14: 6107–6115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bussemakers MJ, van Bokhoven A, Voller M, Smit FP, Schalken JA . The genes for the calcium-dependent cell adhesion molecules P- and E-cadherin are tandemly arranged in the human genome. Biochem Biophys Res Commun 1994; 203: 1291–1294.

    Article  CAS  PubMed  Google Scholar 

  51. Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000; 2: 84–89.

    Article  CAS  PubMed  Google Scholar 

  52. Giroldi LA, Bringuier PP, de Weijert M, Jansen C, van Bokhoven A, Schalken JA . Role of E boxes in the repression of E-cadherin expression. Biochem Biophys Res Commun 1997; 241: 453–458.

    Article  CAS  PubMed  Google Scholar 

  53. Ji X, Woodard AS, Rimm DL, Fearon ER . Transcriptional defects underlie loss of E-cadherin expression in breast cancer. Cell Growth Differ 1997; 8: 773–778.

    CAS  PubMed  Google Scholar 

  54. Cheng JC, Auersperg N, Leung PC . Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells. Oncogene 2011; 30: 3930–3942.

    Article  CAS  PubMed  Google Scholar 

  55. Chang CJ, Chao CH, Xia W, Yang JY, Xiong Y, Li CW et al. p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol 2011; 13: 317–323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Stankiewicz P, Sen P, Bhatt SS, Storer M, Xia Z, Bejjani BA et al. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet 2009; 84: 780–791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shaw-Smith C . Genetic factors in esophageal atresia, tracheo-esophageal fistula and the VACTERL association: roles for FOXF1 and the 16q24.1 FOX transcription factor gene cluster, and review of the literature. Eur J Med Genet 2010; 53: 6–13.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A . p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 1999; 398: 708–713.

    Article  CAS  PubMed  Google Scholar 

  59. Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 1999; 99: 143–153.

    Article  CAS  PubMed  Google Scholar 

  60. Gumbiner BM . Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol 2005; 6: 622–634.

    Article  CAS  PubMed  Google Scholar 

  61. Nilsson J, Helou K, Kovacs A, Bendahl PO, Bjursell G, Ferno M et al. Nuclear Janus-activated kinase 2/nuclear factor 1-C2 suppresses tumorigenesis and epithelial-to-mesenchymal transition by repressing Forkhead box F1. Cancer Res 2010; 70: 2020–2029.

    Article  CAS  PubMed  Google Scholar 

  62. Lo PK, Lee JS, Chen H, Reisman D, Berger FG, Sukumar S . Cytoplasmic mislocalization of overexpressed FOXF1 is associated with the malignancy and metastasis of colorectal adenocarcinomas. Exp Mol Pathol 2013; 94: 262–269.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Correspondence to Y Sasaki or T Tokino.

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Tamura, M., Sasaki, Y., Koyama, R. et al. Forkhead transcription factor FOXF1 is a novel target gene of the p53 family and regulates cancer cell migration and invasiveness. Oncogene 33, 4837–4846 (2014). https://doi.org/10.1038/onc.2013.427

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