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Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer

PI3Ks consist of p110 catalytic subunits and p85 regulatory subunits. PIK3CA, encoding p110α, is frequently mutated in human cancers. Most PIK3CA mutations are clustered in the helical domain or the kinase domain. Here, we report that p85β disassociates from p110α helical domain mutant protein and t...

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Autores principales: Hao, Yujun, He, Baoyu, Wu, Liping, Li, Yamu, Wang, Chao, Wang, Ting, Sun, Longci, Zhang, Yanhua, Zhan, Yangyang, Zhao, Yiqing, Markowitz, Sanford, Veigl, Martina, Conlon, Ronald A., Wang, Zhenghe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007954/
https://www.ncbi.nlm.nih.gov/pubmed/35418124
http://dx.doi.org/10.1038/s41467-022-29585-x
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author Hao, Yujun
He, Baoyu
Wu, Liping
Li, Yamu
Wang, Chao
Wang, Ting
Sun, Longci
Zhang, Yanhua
Zhan, Yangyang
Zhao, Yiqing
Markowitz, Sanford
Veigl, Martina
Conlon, Ronald A.
Wang, Zhenghe
author_facet Hao, Yujun
He, Baoyu
Wu, Liping
Li, Yamu
Wang, Chao
Wang, Ting
Sun, Longci
Zhang, Yanhua
Zhan, Yangyang
Zhao, Yiqing
Markowitz, Sanford
Veigl, Martina
Conlon, Ronald A.
Wang, Zhenghe
author_sort Hao, Yujun
collection PubMed
description PI3Ks consist of p110 catalytic subunits and p85 regulatory subunits. PIK3CA, encoding p110α, is frequently mutated in human cancers. Most PIK3CA mutations are clustered in the helical domain or the kinase domain. Here, we report that p85β disassociates from p110α helical domain mutant protein and translocates into the nucleus through a nuclear localization sequence (NLS). Nuclear p85β recruits deubiquitinase USP7 to stabilize EZH1 and EZH2 and enhances H3K27 trimethylation. Knockout of p85β or p85β NLS mutant reduces the growth of tumors harboring a PIK3CA helical domain mutation. Our studies illuminate a novel mechanism by which PIK3CA helical domain mutations exert their oncogenic function. Finally, a combination of Alpelisib, a p110α-specific inhibitor, and an EZH inhibitor, Tazemetostat, induces regression of xenograft tumors harboring a PIK3CA helical domain mutation, but not tumors with either a WT PIK3CA or a PIK3CA kinase domain mutation, suggesting that the drug combination could be an effective therapeutic approach for PIK3CA helical domain mutant tumors.
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spelling pubmed-90079542022-04-27 Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer Hao, Yujun He, Baoyu Wu, Liping Li, Yamu Wang, Chao Wang, Ting Sun, Longci Zhang, Yanhua Zhan, Yangyang Zhao, Yiqing Markowitz, Sanford Veigl, Martina Conlon, Ronald A. Wang, Zhenghe Nat Commun Article PI3Ks consist of p110 catalytic subunits and p85 regulatory subunits. PIK3CA, encoding p110α, is frequently mutated in human cancers. Most PIK3CA mutations are clustered in the helical domain or the kinase domain. Here, we report that p85β disassociates from p110α helical domain mutant protein and translocates into the nucleus through a nuclear localization sequence (NLS). Nuclear p85β recruits deubiquitinase USP7 to stabilize EZH1 and EZH2 and enhances H3K27 trimethylation. Knockout of p85β or p85β NLS mutant reduces the growth of tumors harboring a PIK3CA helical domain mutation. Our studies illuminate a novel mechanism by which PIK3CA helical domain mutations exert their oncogenic function. Finally, a combination of Alpelisib, a p110α-specific inhibitor, and an EZH inhibitor, Tazemetostat, induces regression of xenograft tumors harboring a PIK3CA helical domain mutation, but not tumors with either a WT PIK3CA or a PIK3CA kinase domain mutation, suggesting that the drug combination could be an effective therapeutic approach for PIK3CA helical domain mutant tumors. Nature Publishing Group UK 2022-04-13 /pmc/articles/PMC9007954/ /pubmed/35418124 http://dx.doi.org/10.1038/s41467-022-29585-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hao, Yujun
He, Baoyu
Wu, Liping
Li, Yamu
Wang, Chao
Wang, Ting
Sun, Longci
Zhang, Yanhua
Zhan, Yangyang
Zhao, Yiqing
Markowitz, Sanford
Veigl, Martina
Conlon, Ronald A.
Wang, Zhenghe
Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer
title Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer
title_full Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer
title_fullStr Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer
title_full_unstemmed Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer
title_short Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer
title_sort nuclear translocation of p85β promotes tumorigenesis of pik3ca helical domain mutant cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007954/
https://www.ncbi.nlm.nih.gov/pubmed/35418124
http://dx.doi.org/10.1038/s41467-022-29585-x
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