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

ABSTRACT: Ubiquitin-conjugating enzyme E2C (UBE2C) mediates 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 report that UBE2C was indeed essential for growth and survival of lung cancer cells harboring Kras mutations, and UBE2C was required for KrasG12D-induced lung tumorigenesis, since Ube2c deletion significantly inhibited tumor formation and extended the lifespan of mice. Mechanistically, KrasG12D induced expression of UBE2C, which coupled with APC/CCDH1 E3 ligase to promote ubiquitylation and degradation of DEPTOR, leading to activation of mTORC signaling. Importantly, DEPTOR levels fluctuated during cell cycle progression in a manner dependent on UBE2C and CDH1, indicating their physiological connection. Finally, Deptor deletion fully rescued 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 and tumor suppressor cascade that regulates cell cycle progression and autophagy and validates UBE2C an attractive target for lung cancer associated with Kras mutations.

SUBMITTER: Zhang S 

PROVIDER: S-EPMC9927933 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature