Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development
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<sup>G12D</sup> 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.
Authors
- Kyung Chan Park (ORCID: https://orcid.org/0000-0002-7730-9466)
- Yo-Han Han (ORCID: https://orcid.org/0000-0002-9349-4366)
- Sang Jeon Chung (ORCID: https://orcid.org/0000-0002-3501-212X)
- Seonghwan Park (ORCID: https://orcid.org/0000-0001-8554-7459)
- Dong Chul Lee (ORCID: https://orcid.org/0009-0008-7177-5205)
- Han Koo (ORCID: https://orcid.org/0000-0003-1165-3173)
- Yeon-Mi You (ORCID: https://orcid.org/0000-0002-3157-5216)
- Hyun Ahm Sohn (ORCID: https://orcid.org/0000-0002-8615-9535)
- Young Il Yeom (ORCID: https://orcid.org/0000-0003-4279-805X)
- Sehoon Park (ORCID: https://orcid.org/0000-0002-4221-2453)
- Dong Joon Kim (ORCID: https://orcid.org/0000-0001-6910-9213)
- Chul‐Ho Lee (ORCID: https://orcid.org/0000-0002-6996-5746)
- Bo‐Kyung Kim (ORCID: https://orcid.org/0000-0003-0863-3008)
- Minho Kang (ORCID: https://orcid.org/0000-0003-0069-026X)
- Yeon-Soo Kim (ORCID: https://orcid.org/0000-0001-9343-7022)
- Zee‐Yong Park (ORCID: https://orcid.org/0000-0002-8184-5982)
- Sang Hyun Min
Institutions
- Chungnam National University (KR)
- Kyungpook National University (KR)
- Gwangju Institute of Science and Technology (KR)
- Korea Research Institute of Bioscience and Biotechnology (KR)
- Sungkyunkwan University (KR)
- Korea University of Science and Technology (KR)
- Dankook University (KR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-16
- DOI
- https://doi.org/10.1038/s41467-024-54476-8
- Citations
- 1
- Primary Topic
- Mechanisms of cancer metastasis
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Research Foundation
- Ministry of Health and Welfare
- Korea Research Institute of Bioscience and Biotechnology
- National Research Foundation of Korea
- Korea Drug Development Fund
- Ministry of Science and ICT, South Korea