1. Academic Validation
  2. The UBE2C/CDH1/DEPTOR axis is an oncogene-tumor suppressor cascade in lung cancer cells

The UBE2C/CDH1/DEPTOR axis is an oncogene-tumor suppressor cascade in lung cancer cells

  • J Clin Invest. 2022 Dec 22;e162434. doi: 10.1172/JCI162434.
Shizhen Zhang 1 Xiahong You 2 Yawen Zheng 3 Yanwen Shen 2 Xiufang Xiong 2 Yi Sun 4
Affiliations

Affiliations

  • 1 Department of Breast Surgery and Oncology, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Cancer Institute, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Zhejiang University School of Medicine, Hangzhou, China.
Abstract

Ubiquitin-conjugating Enzyme E2C (UBE2C) mediates the ubiquitylation chain formation via the K11 linkage. While previous in vitro studies showed that UBE2C plays a growth-promoting role in Cancer cell lines, the underlying mechanism remains elusive. Still unknown is whether and how UBE2C plays a promoting role in vivo. Here we reported that UBE2C is indeed essential for growth and survival of lung Cancer cells harboring Kras mutations, and UBE2C is required for KrasG12D-induced lung tumorigenesis, since Ube2c deletion significantly inhibits tumor formation and extends the life-span of mice. Mechanistically, KrasG12D induces expression of UBE2C, which couples with APC/CCDH1 E3 Ligase to promote ubiquitylation and degradation of DEPTOR, leading to activation of the mTORC signals. Importantly, DEPTOR levels are fluctuated during cell cycle progression in a manner dependent of UBE2C and CDH1, indicating their physiological connection. Finally, Deptor deletion fully rescues the tumor inhibitory effect of Ube2c deletion in the KrasG12D lung tumor model, indicating a causal role of Deptor. Taken together, our study shows that the UBE2C/CDH1/DEPTOR axis forms an oncogene-tumor suppressor cascade that regulates cell cycle progression and Autophagy and validates that UBE2C is an attractive target for lung Cancer associated with Kras mutations.

Keywords

Cell Biology; Lung cancer; Oncology; Ubiquitin-proteosome system.

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