Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai, PR China.
Oncogene. 2015 Jul 23;34(30):3957-67. doi: 10.1038/onc.2014.327. Epub 2014 Oct 6.
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.
癌蛋白 c-Myc 在许多癌症中经常过表达，是癌细胞增殖所必需的。泛素-蛋白酶体依赖性降解是细胞在翻译后水平控制 c-Myc 丰度的主要方式之一。然而，c-Myc 被直接去泛素化的潜在机制尚未完全了解。在这项研究中，通过筛选可能调节 c-Myc 稳定性的泛素特异性蛋白酶 (USP)，我们鉴定了 USP37 作为一种新型去泛素化酶 (DUB)，通过直接结合稳定 c-Myc。USP37 的过表达通过阻止其降解显着增加 c-Myc 的丰度，而 USP37 的耗竭促进 c-Myc 降解并降低 c-Myc 水平。进一步的研究表明，USP37 直接与 c-Myc 相互作用，并以 DUB 活性依赖性方式去泛素化 c-Myc。功能上，USP37 通过调节 c-Myc 水平来调节细胞增殖和瓦伯格效应。临床上，USP37 在人肺癌组织中显着上调，其表达与 c-Myc 蛋白表达呈正相关。因此，我们的研究结果揭示了 USP37 在肺癌中调节 c-Myc 稳定性的先前未被认识的作用，并表明 USP37 可能是治疗肺癌的潜在治疗靶点。
