| First Author | Koo H | Year | 2025 |
| Journal | Nat Commun | Volume | 16 |
| Issue | 1 | Pages | 628 |
| PubMed ID | 39819877 | Mgi Jnum | J:361448 |
| Mgi Id | MGI:7858292 | Doi | 10.1038/s41467-024-54476-8 |
| Citation | Koo H, et al. (2025) Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development. Nat Commun 16(1):628 |
| abstractText | Cancers with activating mutations of KRAS show a high prevalence but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression is post-translationally up-regulated through deubiquitination when the scaffolding function of NDRG3 (N-Myc downstream-regulated gene 3) promotes specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant cancer cells KRAS protein expression, downstream signaling, and cell growth are highly dependent on NDRG3. In conditional Kras(G12D) knock-in mouse models of pancreatic ductal adenocarcinoma, Ndrg3 depletion abolishes Kras protein expression and suppresses intraepithelial neoplasia formation in pancreas. Mechanistically, KRAS protein binds to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through deubiquitination by USP9X recruited to the complex. This interaction can be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that binds KRAS but is defective in USP9X binding, highly suppressing 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. |
