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

Author

Listed:
  • Han Koo

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

  • Kyung Chan Park

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

  • Hyun Ahm Sohn

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Minho Kang

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Dong Joon Kim

    (Dankook University
    Dankook University)

  • Zee-Yong Park

    (Gwangju Institute of Science and Technology)

  • Sehoon Park

    (Gwangju Institute of Science and Technology)

  • Sang Hyun Min

    (Kyungpook National University)

  • Seong-Hwan Park

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Yeon-Mi You

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

  • Yohan Han

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Bo-Kyung Kim

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

  • Chul-Ho Lee

    (University of Science and Technology
    Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Yeon-Soo Kim

    (Chungnam National University)

  • Sang J. Chung

    (Sungkyunkwan University)

  • Young Il Yeom

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology
    Chungnam National University)

  • Dong Chul Lee

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

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.

Suggested Citation

  • 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, 2025. "Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-54476-8
    DOI: 10.1038/s41467-024-54476-8
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    References listed on IDEAS

    as
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