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USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity

Author

Listed:
  • Juan Li

    (Sichuan University)

  • Yang Wang

    (Sichuan University)

  • Yue Luo

    (Sichuan University)

  • Yang Liu

    (Sichuan University)

  • Yong Yi

    (Sichuan University)

  • Jinsong Li

    (Sichuan University)

  • Yang Pan

    (Sichuan University)

  • Weiyuxin Li

    (Sichuan University)

  • Wanbang You

    (Sichuan University)

  • Qingyong Hu

    (Sichuan University)

  • Zhiqiang Zhao

    (Sichuan University)

  • Yujun Zhang

    (Sichuan University)

  • Yang Cao

    (Sichuan University)

  • Lingqiang Zhang

    (Beijing Institute of Lifeomics)

  • Junying Yuan

    (Chinese Academy of Sciences)

  • Zhi-Xiong Jim Xiao

    (Sichuan University
    Sichuan University)

Abstract

Non-small cell lung cancers (NSCLC) frequently contain KRAS mutation but retain wild-type TP53. Abundant senescent cells are observed in premalignant but not in malignant tumors derived from the Kras-driven mouse model, suggesting that KRAS oncogenic signaling would have to overcome the intrinsic senescence burden for cancer progression. Here, we show that the nuclear Beclin 1-mediated inhibition of p53-dependent senescence drives Kras-mediated tumorigenesis. KRAS activates USP5 to stabilize nuclear Beclin 1, leading to MDM2-mediated p53 protein instability. KrasG12D mice lacking Beclin 1 display retarded lung tumor growth. Knockdown of USP5 or knockout of Becn1 leads to increased senescence and reduced autophagy. Mechanistically, KRAS elevates ROS to induce USP5 homodimer formation by forming the C195 disulfide bond, resulting in stabilization and activation of USP5. Together, these results demonstrate that activation of the USP5-Beclin 1 axis is pivotal in overriding intrinsic p53-dependent senescence in Kras-driven lung cancer development.

Suggested Citation

  • Juan Li & Yang Wang & Yue Luo & Yang Liu & Yong Yi & Jinsong Li & Yang Pan & Weiyuxin Li & Wanbang You & Qingyong Hu & Zhiqiang Zhao & Yujun Zhang & Yang Cao & Lingqiang Zhang & Junying Yuan & Zhi-Xio, 2022. "USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35557-y
    DOI: 10.1038/s41467-022-35557-y
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