PTENa/ß paradoxically promote carcinogenesis through WDR5-H3K4me3 axis [RNA-seq]

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