PTENa/b paradoxically promote carcinogenesis through WDR5-H3K4me3 axis [ChIP-seq 2]

We report that USP9X and FBXW11 selectively regulate the stability of PTENa/b but not PTEN proteins by deubiquitination and ubiquitination respectively. USP9X promotes and FBXW11 suppresses tumorigenesis mediated by PTENa/b. In contrast to the current paradigm for PTEN as a tumor suppressor, PTENa/b promote tumorigenesis of cancer cells in a phosphatase-independent manner. Mechanistically, PTENa/b localized in the nucleus regulate expressions of tumor-promoting genes such as NOTCH3 in the similar way as the H3K4 presenter WDR5. Further, PTENa/b but not PTEN directly interact with WDR5 to promote trimethylation of H3K4 and maintain a tumor-promoting signature. To investigate the influence of H3K4me3 at gene promoters with or without PTENa/b depletion by ChIP seq in SMMC-7721.