The ‘New (Nu)-clear’ evidence of the tumor-driving role of PI3K

Abstract

The classical phosphatidylinositol 3-kinases (PI3Ks) are heterodimers of p110 and p85. PIK3CA, the gene encoding the catalytic p110α subunit, is one of the most frequently mutated oncogenes in human cancers. Mutations have been observed to occur in hotspots in the helical domain or kinase domain. Tumors with these two types of PIK3CA mutations show overlapping yet distinct phenotypes; however, the underlying mechanisms driving these phenotypes remain unclear. In a recent publication [1], Hao et al. have revealed exciting findings indicating that the PI3K p85β regulatory subunit promotes cancer progression driven by PIK3CA helical-domain mutations. The authors found that p85β disassociates from the PI3K complex and translocates into the nucleus only in cancer cells bearing PIK3CA helical-domain mutations. Disrupting the nuclear localization of p85β suppresses tumor growth of cancer cells with PIK3CA helical-domain mutation in mice. Mechanistically, the authors have elegantly shown that nuclear p85β recruits the deubiquitinase USP7, which stabilizes the EZH1/2 histone methyltransferases and consequently enhances H3K27 trimethylation and the transcription of genes. Combining an EZH inhibitor with a PI3K inhibitor specifically resulted in regression of mouse xenograft tumors with PIK3CA helical-domain mutations. These findings illustrate a previously uncharacterized function of p85β in tumor development and suggest an effective approach to targeting tumors with PIK3CA helical-domain mutations.