2. Academic Validation
  3. USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity

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

  • Nat Commun. 2022 Dec 17;13(1):7799. doi: 10.1038/s41467-022-35557-y.
Juan Li # 1,  Yang Wang # 2,  Yue Luo 1,  Yang Liu 1,  Yong Yi 1,  Jinsong Li 1,  Yang Pan 1,  Weiyuxin Li 1,  Wanbang You 1,  Qingyong Hu 1,  Zhiqiang Zhao 1,  Yujun Zhang 1,  Yang Cao 1,  Lingqiang Zhang 3,  Junying Yuan 4,  Zhi-Xiong Jim Xiao 5 6
Affiliations

Affiliations

  • 1 Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China.
  • 2 Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China. [email protected].
  • 3 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China.
  • 4 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd, Pudong, Shanghai, 201210, China.
  • 5 Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China. [email protected].
  • 6 State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610041, China. [email protected].
  • # Contributed equally.
PMID: 36528652 DOI: 10.1038/s41467-022-35557-y
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.

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