The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer cells
Shizhen Zhang, … , Xiufang Xiong, Yi Sun
Shizhen Zhang, … , Xiufang Xiong, Yi Sun
Published December 22, 2022
Citation Information: J Clin Invest. 2023;133(4):e162434. https://doi.org/10.1172/JCI162434.
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Research Article Cell biology Oncology

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.

Authors

Shizhen Zhang, Xiahong You, Yawen Zheng, Yanwen Shen, Xiufang Xiong, Yi Sun

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Figure 4

DEPTOR is a cell cycle regulatory protein, controlled by the UBE2C/CDH1 axis.

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DEPTOR is a cell cycle regulatory protein, controlled by the UBE2C/CDH1 ...
(A) Knockdown of UBE2C, CDH1, SAG, and APC2 caused DEPTOR accumulation at the protein level, but not at the mRNA level. A427 cells were transfected with indicated siRNAs followed by IB with the indicated Abs (top), or by RT-qPCR analysis (bottom). (B) Knockdown of CDH1 and UBE2C caused the accumulation of DEPTOR and inactivation of mTORC1/2. A427 cells were transfected with indicated siRNAs followed by IB with the indicated Abs. (C) DEPTOR levels fluctuated during the cell cycle. HeLa cells were arrested at the G1/S phase by double thymidine block (treatment with 2 mM thymidine for 14 hours and release for 9 hours, and then treatment with 2 mM thymidine for another 14 hours), and then released into the normal cell cycle. Cells were harvested at indicated times and analyzed by IB. (D and E) Knockdown of UBE2C and CDH1 abrogated the cell cycle fluctuation of DEPTOR. A427 cells were transfected with siRNA targeting UBE2C (D), CDH1 (E), or siCont for 24 hours, and then cells were synchronized at the G1/S phase by thymidine block and released for the indicated time points. Cells were harvested for IB analysis with indicated Abs (top) or FACS analysis (bottom).