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

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

Abstract 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 functi...

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Main Authors: Han Koo, Kyung Chan Park, Hyun Ahm Sohn, Minho Kang, Dong Joon Kim, Zee-Yong Park, Sehoon Park, Sang Hyun Min, Seong-Hwan Park, Yeon-Mi You, Yohan Han, Bo-Kyung Kim, Chul-Ho Lee, Yeon-Soo Kim, Sang J. Chung, Young Il Yeom, Dong Chul Lee
Format: Article
Language:English
Published: Nature Portfolio 2025-01-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-024-54476-8
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Summary:Abstract 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 KrasG12D 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.
ISSN:2041-1723

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