Prostate-specific oncogene OTUD6A promotes prostatic tumorigenesis via deubiquitinating and stabilizing c-Myc
Prostate-specific oncogene OTUD6A promotes prostatic tumorigenesis via deubiquitinating and stabilizing c-Myc
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DOI：
10.1038/s41418-022-00960-x
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发表时间：
2022-02-25
影响因子：
12.4
通讯作者：
Long, Jiangang
中科院分区：
文献类型：
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作者：
Peng, Yunhua;Liu, Jing;Long, Jiangang
MYC在包括前列腺癌(PrCa)在内的人类肿瘤的发生发展中起重要作用，因此维持高水平c-Myc癌蛋白表达的脱泛素酶(DUB)是一个合理的治疗靶点。已有报道DUB的几个泛素特异性蛋白水解酶(USP)家族成员可去泛素化c-Myc，但这些成员都不是c-Myc在PrCa中的生理学代号。通过对所有DUB的筛选，我们揭示了OTUD6A在PrCa中唯一扩增和过表达，而在其他癌症中不表达，通过去泛素化和稳定c-Myc癌蛋白而诱导前列腺特异性致癌作用。此外，OTUD6A的基因消融通过逆转c-Myc在PrCa中过表达引起的代谢重构，有效地抑制了人PrCa细胞和Hi-Myc转基因PrCa小鼠的前列腺癌的发生。这些结果表明，OTUD6A在PrCa环境中是c-Myc的生理学代号，并通过稳定c-Myc癌蛋白而特异性地促进前列腺癌的发生，提示OTUD6A可能是Myc驱动的PrCa的独特治疗靶点。
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.