Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development

ABSTRACT: Cancers with activating mutations of KRAS show a high prevalence and poor prognosis but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression was post-translationally up-regulated through the deubiquitination of KRAS protein when the scaffolding function of NDRG3 (N-Myc downstream regulated gene 3) promoted specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant pancreatic or lung cancer cells KRAS protein expression, downstream signaling, and cell growth were highly dependent on NDRG3. In conditional KrasG12D knock-in mouse models of pancreatic ductal adenocarcinoma (PDAC), Ndrg3 depletion abolished Kras protein expression in pancreas, and suppressed pancreatic intraepithelial neoplasia (PanIN) formation. Mechanistically, KRAS protein bound to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through the deubiquitination by USP9X recruited to the complex. This interaction could be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that can bind KRAS but is defective in USP9X binding, highly suppressing the KRAS protein expression and KRAS-driven cell growth. In summary, KRAS-driven cancer development critically depends on the deubiquitination of KRAS protein mediated by USP9X/NDRG3, and KRAS-addicted cancers could be effectively targeted by inhibiting the KRAS-NDRG3 interaction.

INSTRUMENT(S): Orbitrap Exploris 240

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Ga Seul Lee  

LAB HEAD: Dong Chul Lee

PROVIDER: PXD051954 | Pride | 2025-05-06

REPOSITORIES: Pride