福克斯A1
EZH2型
癌症研究
泛素
生物
前列腺癌
甲基化
癌症
生物化学
遗传学
基因
乳腺癌
作者
Su H. Park,Ka-wing Fong,Jung Kim,Fang Wang,Xiaodong Lü,Yongik Lee,Lourdes T Brea,Kristine M. Wadosky,Chunming Guo,Sarki A. Abdulkadir,John D. Crispino,Deyu Fang,Panagiotis Ntziachristos,Xin Liu,Xue Li,Yong Wan,David W. Goodrich,Jonathan C. Zhao,Jindan Yu
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2021-04-07
卷期号:7 (15)
被引量:52
标识
DOI:10.1126/sciadv.abe2261
摘要
Forkhead box protein A1 (FOXA1) is essential for androgen-dependent prostate cancer (PCa) growth. However, how FOXA1 levels are regulated remains elusive and its therapeutic targeting proven challenging. Here, we report FOXA1 as a nonhistone substrate of enhancer of zeste homolog 2 (EZH2), which methylates FOXA1 at lysine-295. This methylation is recognized by WD40 repeat protein BUB3, which subsequently recruits ubiquitin-specific protease 7 (USP7) to remove ubiquitination and enhance FOXA1 protein stability. They functionally converge in regulating cell cycle genes and promoting PCa growth. FOXA1 is a major therapeutic target of the inhibitors of EZH2 methyltransferase activities in PCa. FOXA1-driven PCa growth can be effectively mitigated by EZH2 enzymatic inhibitors, either alone or in combination with USP7 inhibitors. Together, our study reports EZH2-catalyzed methylation as a key mechanism to FOXA1 protein stability, which may be leveraged to enhance therapeutic targeting of PCa using enzymatic EZH2 inhibitors.
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