AKT methylation by SETDB1 promotes AKT kinase activity and oncogenic functions.

Abstract

Aberrant activation of Akt disturbs proliferation, survival and metabolic homeostasis of various human cancers. Thus, it is critical to understand upstream signaling pathways governing Akt activation. Here, we report that Akt undergoes SETDB1-mediated lysine-methylation to promote its activation, which is antagonized by the Jumonji-family demethylase, KDM4B. Notably, compared with wild-type mice, mice harboring non-methylated mutant Akt1 not only exhibited reduced body size, but also were less prone to carcinogen-induced skin tumors in part due to reduced Akt activation. Mechanistically, Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) interaction with Akt facilitates its interaction with SETDB1 for subsequent Akt methylation, which in turn sustains Akt phosphorylation. Pathologically, genetic alterations including SETDB1 amplification aberrantly promote Akt methylation to facilitate its activation and oncogenic functions. Thus, Akt methylation is an important step synergizing with PI3K signaling to control Akt activation, suggesting that targeting the SETDB1 signaling could be a potential therapeutic strategy for combatting hyperactive Akt-driven cancers.