RT Journal Article
SR Electronic
T1 Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eabe2261
DO 10.1126/sciadv.abe2261
VO 7
IS 15
A1 Park, Su H.
A1 Fong, Ka-wing
A1 Kim, Jung
A1 Wang, Fang
A1 Lu, Xiaodong
A1 Lee, Yongik
A1 Brea, Lourdes T.
A1 Wadosky, Kristine
A1 Guo, Chunming
A1 Abdulkadir, Sarki A.
A1 Crispino, John D.
A1 Fang, Deyu
A1 Ntziachristos, Panagiotis
A1 Liu, Xin
A1 Li, Xue
A1 Wan, Yong
A1 Goodrich, David W.
A1 Zhao, Jonathan C.
A1 Yu, Jindan
YR 2021
UL http://advances.sciencemag.org/content/7/15/eabe2261.abstract
AB 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.