Methylation of KRAS at lysine 182 and 184 by SETD7 promotes KRAS degradation

Abstract

Oncogenic KRAS mutations are considered to be a key driver for initiation and progression in non-small-cell lung cancer (NSCLC). However, how post-translational modifications (PTMs) of KRAS, especially methylation, modify KRAS activity and downstream signals remain largely unclear. Here, we showed that SET domain containing histone lysine methyltransferase 7 (SETD7) interacts with KRAS and methylates KRAS at lysine 182 and 184. SETD7-mediated methylation of KRAS led to degradation of KRAS and attenuation of the RAS/MEK/ERK signaling cascade, endowing SETD7 with a potent tumor-suppressive role in NSCLC, both in vitro and in vivo. Mechanistically, RABGEF1, a ubiquitin E3 ligase of KRAS, was recruited and promoted KRAS degradation in a K182/K184 methylation-dependent manner. Notably, low SETD7 or RABGEF1 expression was associated with poor prognosis in lung adenocarcinoma patients. Taken together, our results establish a novel connection between lysine methylation and KRAS protein stability, in addition to elucidating a tumor-suppressive function of SETD7 that operates via modulation of oncogenic RAS signaling.