PTENα and PTENβ promote carcinogenesis through WDR5 and H3K4 trimethylation

PTEN alpha and PTEN beta are two longer translational variants of phosphatase and tensin homolog (PTEN) messenger RNA. Their expressional regulations and functions in carcinogenesis remain largely unknown. Here, we demonstrate that, in contrast with the well-established tumour-suppressive role of canonical PTEN, PTEN alpha and PTEN beta promote tumourigenesis by directly interacting with the histone H3 lysine 4 (H3K4) presenter WDR5 to promote H3K4 trimethylation and maintain a tumour-promoting signature. We also show that USP9X and FBXW11 bind to the amino-terminal extensions of PTEN alpha/beta, and respectively deubiquitinate and ubiquitinate lysines 235 and 239 in PTEN alpha to regulate PTEN alpha/beta stability. In accordance, USP9X promotes tumourigenesis and FBXW11 suppresses tumourigenesis through PTEN alpha/beta. Taken together, our results indicate that the Pten gene is a double-edged sword for carcinogenesis, and reinterpretation of the importance of the Pten gene in carcinogenesis is warranted.