学科主题基础医学
FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis
Zhang, Yu; Tong, Tanjun
关键词FOXA1 EZH2 CDKN2A Carcinogenesis
刊名BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
2014-10-10
DOI10.1016/j.bbrc.2014.09.092
453期:1页:172-178
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology ; Biophysics
研究领域[WOS]Biochemistry & Molecular Biology ; Biophysics
关键词[WOS]GENE-EXPRESSION PROFILES ; PROSTATE-CANCER ; CELLULAR SENESCENCE ; ESTROGEN-RECEPTOR ; TRANSCRIPTION ; P16(INK4A) ; CELLS
英文摘要

CDKN2A (p16(INK4a)) is a crucial tumor suppressor involved in many cancers. Our recent investigations revealed that FOXA1 as a forkhead transcription factor mediates CDKN2A activation in cellular senescence. However, the contribution of this axis in carcinogenesis remains unclear. Here, using a comprehensive collection of cancer microarray data, we found FOXA1 is down-regulated in many cancers compared to their normal counterparts and the positive correlation between FOXA1 and CDKN2A could be observed in prostate and breast cancers with lower EZH2 (epigenetic repressor for CDKN2A) expression. Experimentally, epistasis analysis in prostate and breast cancer cells indicated that higher expression of FOXA1 opposes EZH2-mediated CDKN2A repression, as further depletion of FOXA1 reverts the de-silencing of CDKN2A caused by EZH2 inhibition. Concomitantly, EZH2-depletion suppresses cancer cell cycle progression and this regulation is optimized in the presence of FOXA1 and CDKN2A. A further oncogenic transformation assay suggested that overexpression of EZH2 is insufficient to block RAS-induced CDKN2A activation and loss of FOXA1 is mandatory to potentiate EZH2-mediated CDKN2A silencing and to bypass the senescence barrier. Importantly, using an in vitro histone methyltransferase (HMTase) system, we found FOXA1 directly inhibits EZH2′s histone methyltransferase activity through its C-terminal histone binding motif. These data support that positive regulation of CDKN2A by FOXA1 counteracts its tumorigenic repression of by EZH2 in cancers. (C) 2014 Elsevier Inc. All rights reserved.

语种英语
WOS记录号WOS:000343634900029
项目编号81300254 ; 2013CB530801
资助机构National Basic Research Programs of China ; National Key Basic Research Program of China
引用统计
被引频次:14[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/58425
专题北京大学基础医学院_北京大学衰老研究中心
北京大学基础医学院
作者单位Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Res Ctr Aging, Beijing 100191, Peoples R China
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Zhang, Yu,Tong, Tanjun. FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2014,453(1):172-178.
APA Zhang, Yu,&Tong, Tanjun.(2014).FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,453(1),172-178.
MLA Zhang, Yu,et al."FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 453.1(2014):172-178.
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