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CRL3Keap1 E3 ligase facilitates ubiquitin-mediated degradation of oncogenic SRX to suppress colorectal cancer progression

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  • Feng Zhu

    (Fudan University
    Nanjing University of Chinese Medicine)

  • Liangshan Li

    (Fudan University
    Nanjing University of Chinese Medicine)

  • Yuanyuan Chen

    (Shanghai University of Traditional Chinese Medicine)

  • Yongfu Pan

    (Shanghai University of Traditional Chinese Medicine)

  • Wenjuan Zhang

    (Fudan University Shanghai Cancer Center)

  • Lihui Li

    (Shanghai University of Traditional Chinese Medicine)

  • Lili Cai

    (Shanghai University of Traditional Chinese Medicine)

  • Xiaoxue Zhao

    (Shanghai University of Traditional Chinese Medicine)

  • Hu Zhao

    (Fudan University)

  • Shiwen Wang

    (Fudan University
    Nanjing University of Chinese Medicine)

  • Lijun Jia

    (Nanjing University of Chinese Medicine)

Abstract

The antioxidant protein sulfiredoxin-1 (SRX) is an oncogenic factor that promotes tumor progression, but the regulatory mechanism underlying SRX degradation remains to be understood. Herein, we report that Keap1, the substrate-specific adapter of CRL3 complex, specifically binds and promotes the ubiquitin-mediated degradation of SRX at residue K61. Keap1 knockdown accumulates SRX, which in turn facilitates colorectal cancer (CRC) metastasis by activating the activator protein-1/matrix metalloproteinase 9 (AP-1/MMP9) pathway. CRC-associated Keap1 mutants within the BACK domain lose the capability to ubiquitinate SRX and instead promote CRC metastasis. Moreover, inactivation of Keap1 facilitates CRC tumorigenesis and metastasis in mouse models of tumor xenograft due to SRX accumulation. Clinical sample analysis reveals that Keap1 is downregulated while SRX is overexpressed in CRC, which correlates with poor prognosis. Our findings elucidate a mechanism by which CRL3Keap1 ubiquitin ligase degrades SRX to suppress CRC progression, indicating that the Keap1-SRX axis will guide the targeted therapy towards CRC.

Suggested Citation

  • Feng Zhu & Liangshan Li & Yuanyuan Chen & Yongfu Pan & Wenjuan Zhang & Lihui Li & Lili Cai & Xiaoxue Zhao & Hu Zhao & Shiwen Wang & Lijun Jia, 2024. "CRL3Keap1 E3 ligase facilitates ubiquitin-mediated degradation of oncogenic SRX to suppress colorectal cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54919-2
    DOI: 10.1038/s41467-024-54919-2
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    References listed on IDEAS

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    1. Pranavi Koppula & Guang Lei & Yilei Zhang & Yuelong Yan & Chao Mao & Lavanya Kondiparthi & Jiejun Shi & Xiaoguang Liu & Amber Horbath & Molina Das & Wei Li & Masha V. Poyurovsky & Kellen Olszewski & B, 2022. "A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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