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

Yujun Hao (), Baoyu He, Liping Wu, Yamu Li, Chao Wang, Ting Wang, Longci Sun, Yanhua Zhang, Yangyang Zhan, Yiqing Zhao, Sanford Markowitz, Martina Veigl, Ronald A. Conlon and Zhenghe Wang ()
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Yujun Hao: Shanghai Jiao Tong University School of Medicine
Baoyu He: Shanghai Jiao Tong University School of Medicine
Liping Wu: Case Western Reserve University
Yamu Li: Case Western Reserve University
Chao Wang: Case Western Reserve University
Ting Wang: Shanghai Jiao Tong University School of Medicine
Longci Sun: Shanghai Jiao Tong University School of Medicine
Yanhua Zhang: Shanghai Jiao Tong University School of Medicine
Yangyang Zhan: Shanghai Jiao Tong University School of Medicine
Yiqing Zhao: Case Western Reserve University
Sanford Markowitz: Case Western Reserve University
Martina Veigl: Case Western Reserve University
Ronald A. Conlon: Case Western Reserve University
Zhenghe Wang: Case Western Reserve University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29585-x

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