https://scholars.lib.ntu.edu.tw/handle/123456789/575362
標題: | Estrogen-mediated epigenetic repression of the imprinted gene cyclin-dependent kinase inhibitor 1C in breast cancer cells | 作者: | Rodriguez B.A.T. Weng Y.-I. Liu T.-M. Zuo T. Hsu P.-Y. CHING-HUNG LIN ANN-LII CHENG Cui H. Yan P.S. Huang T.H.-M. |
公開日期: | 2011 | 出版社: | Oxford University Press | 卷: | 32 | 期: | 6 | 起(迄)頁: | 812-821 | 來源出版物: | Carcinogenesis | 摘要: | While tumor suppressor genes frequently undergo epigenetic silencing in cancer, how the instructions directing this transcriptional repression are transmitted in cancer cells remain largely unclear. Expression of cyclin-dependent kinase inhibitor 1C (CDKN1C), an imprinted gene on chromosomal band 11 p15.5, is reduced or lost in the majority of breast cancers. Here, we report that CDKN1C is suppressed by estrogen through epigenetic mechanisms involving the chromatin-interacting noncoding RNA KCNQ1OT1 and CCCTC-binding factor (CTCF). Activation of estrogen signaling reduced CDKN1C expression 3-fold (P < 0.001) and established repressive histone modifications at the 5′ regulatory region of the locus. These events were concomitant with induction of KCNQ1OT1 expression as well as increased recruitment of CTCF to both the distal KCNQ1OT1 promoter-associated imprinting control region (ICR) and the CDKN1C locus. Transient depletion of CTCF by small interfering RNA increased CDKN1C expression and significantly reduced the estrogen-mediated repression of CDKN1C. Further studies in breast cancer cell lines indicated that the epigenetic silencing of CDKN1C occurs in part as the result of genetic loss of the inactive methylated 11p15.5 ICR allele (R2 = 0.612, P < 0.001). We also found a novel cis-encoded antisense transcript, CDKN1C-AS, which is induced by estrogen signaling following pharmacologic inhibition of DNA methyltransferase and histone deacetylase activity. Forced expression of CDKN1C-AS was capable of repressing endogenous CDKN1C in vivo. Our findings suggest that in addition to promoter hypermethylation, epigenetic repression of tumor suppressor genes by CTCF and noncoding RNA transcripts could be more common and important than previously understood. Published by Oxford University Press 2011. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-79958187564&doi=10.1093%2fcarcin%2fbgr017&partnerID=40&md5=9bf393d76a96d0ae7c81a53b266da894 https://scholars.lib.ntu.edu.tw/handle/123456789/575362 |
ISSN: | 0143-3334 | DOI: | 10.1093/carcin/bgr017 | SDG/關鍵字: | cyclin dependent kinase inhibitor 1C; DNA methyltransferase; estrogen; histone deacetylase; small interfering RNA; transcription factor CTCF; untranslated RNA; article; breast cancer; cancer cell; enzyme activity; enzyme inhibition; epigenetics; gene locus; gene loss; gene repression; gene silencing; genome imprinting; histone modification; human; human cell; human tissue; priority journal; protein expression; signal transduction |
顯示於: | 醫學系 |
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