Abstract
The oncoprotein c-Myc is frequently overexpressed in many cancers and is essential for cancer cell proliferation. Ubiquitin-proteasome-dependent degradation is one of the main ways in which cells control c-Myc abundance at a post-translational level. However, the underlying mechanism by which c-Myc is directly deubiquitinated is not fully understood. In this study, by screening ubiquitin-specific proteases (USPs) that may regulate c-Myc stability, we identified USP37 as a novel deubiquitinating enzyme (DUB) that stabilizes c-Myc via direct binding. The overexpression of USP37 markedly increases c-Myc abundance by blocking its degradation, whereas the depletion of USP37 promotes c-Myc degradation and reduces c-Myc levels. Further studies indicate that USP37 directly interacts with c-Myc and deubiquitinates c-Myc in a DUB activity-dependent manner. Functionally, USP37 regulates cell proliferation and the Warburg effect by regulating c-Myc levels. Clinically, USP37 is significantly upregulated in human lung cancer tissues, where its expression is positively correlated with c-Myc protein expression. Thus, our findings uncover a previously unrecognized role for USP37 in the regulation of c-Myc stability in lung cancer and suggest that USP37 might be a potential therapeutic target for the treatment of lung cancer.
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Acknowledgements
We thank other members of the Wang laboratory for their assistance. This work was supported by grants from the National Basic Research Program of China (973 program 2010CB529704 and 2012CB910404), the National Natural Science Foundation of China (30800587, 30971521 and 31171338), the Science and Technology Commission of Shanghai Municipality (11DZ2260300) and the Doctoral Fund of Ministry of Education of China (20130076110022). PW is a scholar of the Shanghai Rising-Star Program from the Science and Technology Commission of Shanghai Municipality (09QA1401900 and 13QH1401), the Program for New Century Excellent Talents in University (NCET-10-0387) and the Dawn Program of Shanghai Education Commission (11SG27).
Author Contributions
JP, QD, JC and PW designed the research; JP, QD, JC, XW, TN, HL, JJ, TC, PW, XC and XY performed the experiments; JP, QD, JC, XW and LM analyzed the data; JP, JX and PW wrote the paper.
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Pan, J., Deng, Q., Jiang, C. et al. USP37 directly deubiquitinates and stabilizes c-Myc in lung cancer. Oncogene 34, 3957–3967 (2015). https://doi.org/10.1038/onc.2014.327
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DOI: https://doi.org/10.1038/onc.2014.327
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