Nuclear translocation of p85 beta promotes tumorigenesis of PIK3CA helical domain mutant cancer

PI3Ks consist of p110 catalytic subunits and p85 regulatory subunits. PIK3CA, encoding p110 alpha, is frequently mutated in human cancers. Most PIK3CA mutations are clustered in the helical domain or the kinase domain. Here, we report that p85 beta disassociates from p110 alpha helical domain mutant protein and translocates into the nucleus through a nuclear localization sequence (NLS). Nuclear p85 beta recruits deubiquitinase USP7 to stabilize EZH1 and EZH2 and enhances H3K27 trimethylation. Knockout of p85 beta or p85 beta 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 p110 alpha-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. The mechanisms behind the oncogenic role of the PIK3CA helical domain mutant is poorly understood. Here, the authors show that its oncogenic function depends on the release of p85 beta from mutated p110 alpha, its translocation to the nucleus and the consequent increased activity of EZH proteins.