Aberrant TGFβ/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor, Runx1T1 in ovarian cancer

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Title:	Aberrant TGFβ/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor, Runx1T1 in ovarian cancer
Authors:	Yeh, K.-T.alm, Chen, T.-H.b, Yang, H.-W.cd, Chou, J.-L.cd, Chen, L.-Y.cd, Yeh, C.-M.c, Chen, Y.-H.f, Lin, R.-I.gh, Su, H.-Y.cd, Chen, G.C.W.i, Deatherage, D.E.i, Huang, Y.-W.i, Yan, P.S.i, Lin, H.-J.ij, Nephew, K.P.k, Huang, T.H.M.i, Lai, H.-C.gh, Chan, M.W.Y.c
Contributors:	Department of Life Sciences, Tunghai University
Keywords:	Epigenetics;Ovarian cancer;RunX1T1;TGFβ
Date:	2011
Issue Date:	2013-05-24T09:12:52Z (UTC)
Abstract:	h Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan i Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Taiwan j Division of Medical Technology, School of Allied Medical Professions, Ohio State University, Columbus, OH, Taiwan k Medical Sciences, Indiana University School of Medicine, Bloomington, IN, United States l Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan m School of Medicine; Chung Shan Medical University, Taichung, Taiwan View additional affiliations Retrieving additional affiliations... -------------------------------------------------------------------------------- View references (46) Abstract Aberrant TGFβ signaling pathway may alter the expression of down-stream targets and promotes ovarian carcinogenesis. However, the mechanism of this impairment is not fully understood. Our previous study has identified RunX1T1 as a putative SMAD4 target in an immortalized ovarian surface epithelial cell line, IOSE. In this study, we report that transcription of RunX1T1 was confirmed to be positively regulated by SMAD4 in IOSE cells and epigenetically silenced in a panel of ovarian cancer cell lines by promoter hypermethylation and histone methylation at H3 lysine 9. SMAD4 depletion increased repressive histone modifications of RunX1T1 promoter without affecting promoter methylation in IOSE cells. Epigenetic treatment can restore RunX1T1 expression by reversing its epigenetic status in MCP3 ovarian cancer cells. When transiently treated with a demethylating agent, the expression of RunX1T1 was partially restored in MCP3 cells, but gradual re-silencing through promoter re-methylation was observed after the treatment. Interestingly, SMAD4 knockdown accelerated this re-silencing process, suggesting that normal TGFβ signaling is essential for the maintenance of RunX1T1 expression. In vivo analysis confirmed that hypermethylation of RunX1T1 was detected in 35.7% (34/95) of ovarian tumors with high clinical stages (p = 0.035) and in 83% (5/6) of primary ovarian cancer-initiating cells. Additionally, concurrent methylation of RunX1T1 and another SMAD4 target, FBXO32 which was previously found to be hypermethylated in ovarian cancer was observed in this same sample cohort (p < 0.05). Restoration of RunX1T1 inhibited cancer cell growth. Taken together, dysregulated TGFβ/SMAD4 signaling may lead to epigenetic silencing of a putative tumor suppressor, RunX1T1, during ovarian carcinogenesis. ? 2011 Landes Bioscience.
Relation:	Epigenetics Volume 6, Issue 6, June 2011, Pages 727-739
Appears in Collections:	[生命科學系所] 期刊論文

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