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

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 met...

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Autores principales: Park, Su H., Fong, Ka-wing, Kim, Jung, Wang, Fang, Lu, Xiaodong, Lee, Yongik, Brea, Lourdes T., Wadosky, Kristine, Guo, Chunming, Abdulkadir, Sarki A., Crispino, John D., Fang, Deyu, Ntziachristos, Panagiotis, Liu, Xin, Li, Xue, Wan, Yong, Goodrich, David W., Zhao, Jonathan C., Yu, Jindan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026124/
https://www.ncbi.nlm.nih.gov/pubmed/33827814
http://dx.doi.org/10.1126/sciadv.abe2261
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author Park, Su H.
Fong, Ka-wing
Kim, Jung
Wang, Fang
Lu, Xiaodong
Lee, Yongik
Brea, Lourdes T.
Wadosky, Kristine
Guo, Chunming
Abdulkadir, Sarki A.
Crispino, John D.
Fang, Deyu
Ntziachristos, Panagiotis
Liu, Xin
Li, Xue
Wan, Yong
Goodrich, David W.
Zhao, Jonathan C.
Yu, Jindan
author_facet Park, Su H.
Fong, Ka-wing
Kim, Jung
Wang, Fang
Lu, Xiaodong
Lee, Yongik
Brea, Lourdes T.
Wadosky, Kristine
Guo, Chunming
Abdulkadir, Sarki A.
Crispino, John D.
Fang, Deyu
Ntziachristos, Panagiotis
Liu, Xin
Li, Xue
Wan, Yong
Goodrich, David W.
Zhao, Jonathan C.
Yu, Jindan
author_sort Park, Su H.
collection PubMed
description 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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spelling pubmed-80261242021-04-21 Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer Park, Su H. Fong, Ka-wing Kim, Jung Wang, Fang Lu, Xiaodong Lee, Yongik Brea, Lourdes T. Wadosky, Kristine Guo, Chunming Abdulkadir, Sarki A. Crispino, John D. Fang, Deyu Ntziachristos, Panagiotis Liu, Xin Li, Xue Wan, Yong Goodrich, David W. Zhao, Jonathan C. Yu, Jindan Sci Adv Research Articles 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. American Association for the Advancement of Science 2021-04-07 /pmc/articles/PMC8026124/ /pubmed/33827814 http://dx.doi.org/10.1126/sciadv.abe2261 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Park, Su H.
Fong, Ka-wing
Kim, Jung
Wang, Fang
Lu, Xiaodong
Lee, Yongik
Brea, Lourdes T.
Wadosky, Kristine
Guo, Chunming
Abdulkadir, Sarki A.
Crispino, John D.
Fang, Deyu
Ntziachristos, Panagiotis
Liu, Xin
Li, Xue
Wan, Yong
Goodrich, David W.
Zhao, Jonathan C.
Yu, Jindan
Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer
title Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer
title_full Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer
title_fullStr Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer
title_full_unstemmed Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer
title_short Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer
title_sort posttranslational regulation of foxa1 by polycomb and bub3/usp7 deubiquitin complex in prostate cancer
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026124/
https://www.ncbi.nlm.nih.gov/pubmed/33827814
http://dx.doi.org/10.1126/sciadv.abe2261
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