Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer

Su H. Park, Ka Wing Fong, Jung Kim, Fang Wang, Xiaodong Lu, Yongik Lee, Lourdes T. Brea, Kristine 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

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37 Scopus citations


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.

Original languageEnglish
Article numbereabe2261
JournalScience advances
Issue number15
StatePublished - Apr 7 2021

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