PTEN-alpha and PTEN-beta promote carcinogenesis through WDR5 and H3K4 trimethylation
Menée notamment à l'aide de xénogreffes sur un modèle murin et à partir de l'analyse immunohistochimique d'échantillons de tumeurs hépatiques et de tissus adjacents, cette étude met en évidence un mécanisme par lequel les phosphatases PTEN-alpha et PTEN-bêta favorisent la carcinogenèse via la triméthylation de la lysine 4 de l'histone H3 de la protéine WDR5
PTENα and PTENβ 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, PTENα and PTENβ 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 PTENα/β, and respectively deubiquitinate and ubiquitinate lysines 235 and 239 in PTENα to regulate PTENα/β stability. In accordance, USP9X promotes tumourigenesis and FBXW11 suppresses tumourigenesis through PTENα/β. 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.