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Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells

Oncogene volume 30, pages 3930–3942 (2011)Cite this article

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Abstract

The mechanisms underlying the progression of noninvasive serous borderline ovarian tumors (SBOT) to low-grade invasive carcinomas are poorly understood. We recently showed that inhibition of p53 induces SBOT invasion by activating the PI3K/Akt pathway and transcriptionally repressing E-cadherin. In human cancers, aberrant DNA methylation is a common phenomenon, and it is thought to be involved in the progression from noninvasive to invasive ovarian carcinomas. In this study, we tested the hypothesis that inhibition of p53 downregulates E-cadherin by regulating the methylation of its promoter in SBOT cells. Here, we show that DNA methyltransferase-1 (DNMT1), but not DNMT3a or DNMT3b, was increased in SV40 LT-infected SBOT4 cells, SBOT4-LT and the low-grade invasive serous ovarian carcinoma-derived cell line MPSC1. Treatment with 5-Aza-dC, a DNMT1 inhibitor, restored E-cadherin promoter methylation and expression, and inhibited cell invasion in both invasive SBOT4-LT and MPSC1 cells. Moreover, knockdown of endogenous p53 using siRNA in SBOT3.1 cells induced DNMT1 expression and led to an increase in E-cadherin promoter methylation. Additionally, activation of the PI3K/Akt pathway is required for p53 inhibition-induced DNMT1 expression. The increase in DNMT1 was associated with the inhibition of p53-induced downregulation of E-cadherin and cell invasion. Our findings show an important role for p53 in the progression of SBOT to an invasive carcinoma, and suggest that downregulation of E-cadherin by DNMT1-mediated promoter methylation contributes to this process.

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References

  • Ahluwalia A, Hurteau JA, Bigsby RM, Nephew KP . (2001). DNA methylation in ovarian cancer. II. Expression of DNA methyltransferases in ovarian cancer cell lines and normal ovarian epithelial cells. Gynecol Oncol 82: 299–304.

    Article  CAS  PubMed  Google Scholar 

  • Asadollahi R, Hyde CA, Zhong XY . (2010). Epigenetics of ovarian cancer: from the lab to the clinic. Gynecol Oncol 118: 81–87.

    Article  CAS  PubMed  Google Scholar 

  • Astanehe A, Arenillas D, Wasserman WW, Leung PC, Dunn SE, Davies BR et al. (2008). Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer. J Cell Sci 121: 664–674.

    Article  CAS  PubMed  Google Scholar 

  • Balch C, Fang F, Matei DE, Huang TH, Nephew KP . (2009). Minireview: epigenetic changes in ovarian cancer. Endocrinology 150: 4003–4011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benton G, Crooke E, George J . (2009). Laminin-1 induces E-cadherin expression in 3-dimensional cultured breast cancer cells by inhibiting DNA methyltransferase 1 and reversing promoter methylation status. FASEB J 23: 3884–3895.

    Article  CAS  PubMed  Google Scholar 

  • Bestor TH . (2000). The DNA methyltransferases of mammals. Hum Mol Genet 9: 2395–2402.

    Article  CAS  PubMed  Google Scholar 

  • Bird AP . (1980). DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res 8: 1499–1504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonome T, Lee JY, Park DC, Radonovich M, Pise-Masison C, Brady J et al. (2005). Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary. Cancer Res 65: 10602–10612.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Cheng JC, Auersperg N, Leung PC . (2011). Inhibition of p53 induces invasion of serous borderline ovarian tumor cells by accentuating PI3K/Akt-mediated suppression of E-cadherin. Oncogene 30: 1020–1031.

    Article  CAS  PubMed  Google Scholar 

  • Cheng P, Schmutte C, Cofer KF, Felix JC, Yu MC, Dubeau L . (1997). Alterations in DNA methylation are early, but not initial, events in ovarian tumorigenesis. Br J Cancer 75: 396–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christofori G, Semb H . (1999). The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci 24: 73–76.

    Article  CAS  PubMed  Google Scholar 

  • Darai E, Scoazec JY, Walker-Combrouze F, Mlika-Cabanne N, Feldmann G, Madelenat P et al. (1997). Expression of cadherins in benign, borderline, and malignant ovarian epithelial tumors: a clinicopathologic study of 60 cases. Hum Pathol 28: 922–928.

    Article  CAS  PubMed  Google Scholar 

  • Fan H, Zhao Z, Quan Y, Xu J, Zhang J, Xie W . (2007). DNA methyltransferase 1 knockdown induces silenced CDH1 gene reexpression by demethylation of methylated CpG in hepatocellular carcinoma cell line SMMC-7721. Eur J Gastroenterol Hepatol 19: 952–961.

    Article  CAS  PubMed  Google Scholar 

  • Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M . (2004). PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30: 193–204.

    Article  PubMed  Google Scholar 

  • Gershenson DM, Silva EG, Tortolero-Luna G, Levenback C, Morris M, Tornos C . (1998). Serous borderline tumors of the ovary with noninvasive peritoneal implants. Cancer 83: 2157–2163.

    Article  CAS  PubMed  Google Scholar 

  • Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF et al. (1995). E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 55: 5195–5199.

    CAS  PubMed  Google Scholar 

  • Graff JR, Herman JG, Myohanen S, Baylin SB, Vertino PM . (1997). Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation. J Biol Chem 272: 22322–22329.

    Article  CAS  PubMed  Google Scholar 

  • Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, van Roy F, Lee-Kwon W et al. (2003). The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 63: 2172–2178.

    CAS  PubMed  Google Scholar 

  • Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . (1996). Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93: 9821–9826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hudson LG, Zeineldin R, Stack MS . (2008). Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression. Clin Exp Metastasis 25: 643–655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones PA, Baylin SB . (2002). The fundamental role of epigenetic events in cancer. Nat Rev Genet 3: 415–428.

    Article  CAS  PubMed  Google Scholar 

  • Laird PW, Jackson-Grusby L, Fazeli A, Dickinson SL, Jung WE, Li E et al. (1995). Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81: 197–205.

    Article  CAS  PubMed  Google Scholar 

  • Larue L, Bellacosa A . (2005). Epithelial–mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene 24: 7443–7454.

    Article  CAS  PubMed  Google Scholar 

  • Lee JM, Dedhar S, Kalluri R, Thompson EW . (2006). The epithelial–mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172: 973–981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JO, Kwun HJ, Jung JK, Choi KH, Min DS, Jang KL . (2005). Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1. Oncogene 24: 6617–6625.

    Article  CAS  PubMed  Google Scholar 

  • Leonhardt H, Page AW, Weier HU, Bestor TH . (1992). A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71: 865–873.

    Article  CAS  PubMed  Google Scholar 

  • Leu YW, Rahmatpanah F, Shi H, Wei SH, Liu JC, Yan PS et al. (2003). Double RNA interference of DNMT3b and DNMT1 enhances DNA demethylation and gene reactivation. Cancer Res 63: 6110–6115.

    CAS  PubMed  Google Scholar 

  • MacLeod AR, Szyf M . (1995). Expression of antisense to DNA methyltransferase mRNA induces DNA demethylation and inhibits tumorigenesis. J Biol Chem 270: 8037–8043.

    Article  CAS  PubMed  Google Scholar 

  • Makarla PB, Saboorian MH, Ashfaq R, Toyooka KO, Toyooka S, Minna JD et al. (2005). Promoter hypermethylation profile of ovarian epithelial neoplasms. Clin Cancer Res 11: 5365–5369.

    Article  CAS  PubMed  Google Scholar 

  • Okano M, Bell DW, Haber DA, Li E . (1999). DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99: 247–257.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • Peterson EJ, Bogler O, Taylor SM . (2003). p53-mediated repression of DNA methyltransferase 1 expression by specific DNA binding. Cancer Res 63: 6579–6582.

    CAS  PubMed  Google Scholar 

  • Pohl G, Ho CL, Kurman RJ, Bristow R, Wang TL, Shih Ie M . (2005). Inactivation of the mitogen-activated protein kinase pathway as a potential target-based therapy in ovarian serous tumors with KRAS or BRAF mutations. Cancer Res 65: 1994–2000.

    Article  CAS  PubMed  Google Scholar 

  • Rahnama F, Shafiei F, Gluckman PD, Mitchell MD, Lobie PE . (2006). Epigenetic regulation of human trophoblastic cell migration and invasion. Endocrinology 147: 5275–5283.

    Article  CAS  PubMed  Google Scholar 

  • Rahnama F, Thompson B, Steiner M, Shafiei F, Lobie PE, Mitchell MD . (2009). Epigenetic regulation of E-cadherin controls endometrial receptivity. Endocrinology 150: 1466–1472.

    Article  CAS  PubMed  Google Scholar 

  • Ramchandani S, MacLeod AR, Pinard M, von Hofe E, Szyf M . (1997). Inhibition of tumorigenesis by a cytosine-DNA, methyltransferase, antisense oligodeoxynucleotide. Proc Natl Acad Sci USA 94: 684–689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Risinger JI, Berchuck A, Kohler MF, Boyd J . (1994). Mutations of the E-cadherin gene in human gynecologic cancers. Nat Genet 7: 98–102.

    Article  CAS  PubMed  Google Scholar 

  • Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA et al. (1999). The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 27: 2291–2298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schuijer M, Berns EM . (2003). TP53 and ovarian cancer. Hum Mutat 21: 285–291.

    Article  CAS  PubMed  Google Scholar 

  • Sheng S, Qiao M, Pardee AB . (2009). Metastasis and AKT activation. J Cell Physiol 218: 451–454.

    Article  CAS  PubMed  Google Scholar 

  • Shieh YS, Shiah SG, Jeng HH, Lee HS, Wu CW, Chang LC . (2005). DNA methyltransferase 1 expression and promoter methylation of E-cadherin in mucoepidermoid carcinoma. Cancer 104: 1013–1021.

    Article  CAS  PubMed  Google Scholar 

  • Shih Ie M, Kurman RJ . (2004). Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol 164: 1511–1518.

    Article  PubMed  Google Scholar 

  • Singer G, Stohr R, Cope L, Dehari R, Hartmann A, Cao DF et al. (2005). Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation. Am J Surg Pathol 29: 218–224.

    Article  PubMed  Google Scholar 

  • Sun L, Zhao H, Xu Z, Liu Q, Liang Y, Wang L et al. (2007). Phosphatidylinositol 3-kinase/protein kinase B pathway stabilizes DNA methyltransferase I protein and maintains DNA methylation. Cell Signal 19: 2255–2263.

    Article  CAS  PubMed  Google Scholar 

  • Tam KF, Liu VW, Liu SS, Tsang PC, Cheung AN, Yip AM et al. (2007). Methylation profile in benign, borderline and malignant ovarian tumors. J Cancer Res Clin Oncol 133: 331–341.

    Article  CAS  PubMed  Google Scholar 

  • Van Aken E, De Wever O, Correia da Rocha AS, Mareel M . (2001). Defective E-cadherin/catenin complexes in human cancer. Virchows Arch 439: 725–751.

    Article  CAS  PubMed  Google Scholar 

  • Veatch AL, Carson LF, Ramakrishnan S . (1994). Differential expression of the cell–cell adhesion molecule E-cadherin in ascites and solid human ovarian tumor cells. Int J Cancer 58: 393–399.

    Article  CAS  PubMed  Google Scholar 

  • Vergara D, Tinelli A, Martignago R, Malvasi A, Chiuri VE, Leo G . (2010). Biomolecular pathogenesis of borderline ovarian tumors: focusing target discovery through proteogenomics. Curr Cancer Drug Targets 10: 107–116.

    Article  CAS  PubMed  Google Scholar 

  • Vogelstein B, Lane D, Levine AJ . (2000). Surfing the p53 network. Nature 408: 307–310.

    Article  CAS  PubMed  Google Scholar 

  • Woo MM, Salamanca CM, Minor A, Auersperg N . (2007). An improved assay to quantitate the invasiveness of cells in modified Boyden chambers. In vitro Cell Dev Biol Anim 43: 7–9.

    Article  PubMed  Google Scholar 

  • Wu J, Issa JP, Herman J, Bassett Jr DE, Nelkin BD, Baylin SB . (1993). Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells. Proc Natl Acad Sci USA 90: 8891–8895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshiura K, Kanai Y, Ochiai A, Shimoyama Y, Sugimura T, Hirohashi S . (1995). Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc Natl Acad Sci USA 92: 7416–7419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research to PCKL and National Cancer Institute of Canada with funds from the Canadian Cancer Society to NA. PCKL is the recipient of a Child & Family Research Institute Distinguished Investigator Award. JCC is the recipient of four year fellowships for PhD students from University of British Columbia.

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  1. Department of Obstetrics and Gynecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada

    J-C Cheng, N Auersperg & P C K Leung

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  1. J-C Cheng
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Correspondence to P C K Leung.

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Cheng, JC., Auersperg, N. & Leung, P. Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells. Oncogene 30, 3930–3942 (2011). https://doi.org/10.1038/onc.2011.117

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