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

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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
Volume7
Issue number15
DOIs
StatePublished - Apr 7 2021

Bibliographical note

Funding Information:
Mass spectrometry services were provided by the Taplin Mass Spectrometry Facility, Harvard Medical School, and Northwestern Proteomics Core Facility, supported by NCI CCSG P30CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award (S100D025194) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics (P41 GM108569). This work was supported in part by the NIH/ NCI training grant T32CA09560 (to S.H.P.), the American Cancer Society IRG-18-163-24 (to K.-w.F.), R01CA172384 and R01CA227918 (to J.Y.), PCa SPORE P50CA180995 (to J.Y.), R50CA211271 (to J.C.Z.), R01CA234162 (to D.W.G.), R01CA207757 (to D.W.G.), R01DK110477(to X. Li), GM121662 (to X. Liu), GM136308 (to X. Liu), Welch Foundation research grant I-1790 (to X. Liu), Department of Defense grants W81XWH-17-1-0405 and W81XWH-17-1-0578 (to J.Y.), and Prostate Cancer Foundation 2017CHAL2008 (to J.Y. and J.C.Z.).

Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved.

ASJC Scopus subject areas

  • General

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