Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
Cell Death Differ. 2022 Sep;29(9):1730-1743. doi: 10.1038/s41418-022-00960-x. Epub 2022 Feb 25.
MYC drives the tumorigenesis of human cancers, including prostate cancer (PrCa), thus deubiquitinase (DUB) that maintains high level of c-Myc oncoprotein is a rational therapeutic target. Several ubiquitin-specific protease (USP) family members of DUB have been reported to deubiquitinate c-Myc, but none of them is the physiological DUB for c-Myc in PrCa. By screening all the DUBs, here we reveal that OTUD6A is exclusively amplified and overexpressed in PrCa but not in other cancers, eliciting a prostatic-specific oncogenic role through deubiquitinating and stabilizing c-Myc oncoprotein. Moreover, genetic ablation of OTUD6A efficiently represses prostatic tumorigenesis of both human PrCa cells and the Hi-Myc transgenic PrCa mice, via reversing the metabolic remodeling caused by c-Myc overexpression in PrCa. These results indicate that OTUD6A is a physiological DUB for c-Myc in PrCa setting and specifically promotes prostatic tumorigenesis through stabilizing c-Myc oncoprotein, suggesting that OTUD6A could be a unique therapeutic target for Myc-driven PrCa.
MYC 驱动人类癌症的肿瘤发生，包括前列腺癌（PrCa），因此维持 c-Myc 癌蛋白高水平的去泛素化酶（DUB）是一个合理的治疗靶点。已经报道了几种 DUB 的泛素特异性蛋白酶（USP）家族成员可以去泛素化 c-Myc，但它们都不是 PrCa 中 c-Myc 的生理 DUB。通过筛选所有的 DUB，我们在这里揭示 OTUD6A 仅在 PrCa 中扩增和过度表达，而不在其他癌症中表达，通过去泛素化和稳定 c-Myc 癌蛋白，引发前列腺特异性致癌作用。此外，OTUD6A 的遗传缺失有效地抑制了人 PrCa 细胞和 Hi-Myc 转基因 PrCa 小鼠的前列腺肿瘤发生，通过逆转 c-Myc 在 PrCa 中过度表达引起的代谢重塑。这些结果表明，OTUD6A 是 PrCa 中 c-Myc 的生理 DUB，并通过稳定 c-Myc 癌蛋白特异性地促进前列腺肿瘤发生，提示 OTUD6A 可能是 Myc 驱动的 PrCa 的独特治疗靶点。
