PTENα/β paradoxically promote carcinogenesis through WDR5-H3K4me3 axis [RNA-seq]

we report that USP9X and FBXW11 selectively regulate the stability of PTENα/β but not PTEN proteins by deubiqitination and ubiquitination respectively. USP9X promotes and FBXW11 suppresses tumorigenesis mediated by PTENα/β. In contrast to the current paradigm for PTEN as a tumor suppressor, PTENα/β promote tumorigenesis of cancer cells in a phosphatase-independent manner. Mechanistically, PTENα/β localized in the nucleus regulate expressions of tumor-promoting genes such as NOTCH3 in the similar way as the H3K4 presenter WDR5. Further, PTENα/β but not PTEN directly interact with WDR5 to promote trimethylation of H3K4 and maintain a tumor-promoting signature. RNA sequencing in parental and PTENα/βKO-1 SMMC-7721 cell lines with or without USP9X depletion by two independent experiments; RNA sequencing in MiaPaCa2 cell lines with or without PTENα/β