Amplification of Glyceronephosphate O-Acyltransferase and Recruitment of USP30 Stabilize DRP1 to Promote Hepatocarcinogenesis
Amplification of Glyceronephosphate O-Acyltransferase and Recruitment of USP30 Stabilize DRP1 to Promote Hepatocarcinogenesis
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DOI：
10.1158/0008-5472.can-18-0340
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发表时间：
2018-10-15
期刊：
影响因子：
11.2
通讯作者：
Li, Youjun
中科院分区：
文献类型：
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作者：
Gu, Li;Zhu, Yahui;Li, Youjun
肝细胞癌（HCC）是世界范围内癌症相关死亡的主要原因，并且HCC的潜在病理生理学非常复杂。在这项研究中，我们报告说，在2,783个编码代谢酶的基因的生物信息学筛选中，编码甘油磷酸O-酰基转移酶的GNPAT被扩增、上调，并且与HCC患者的不良临床结局高度相关。GNPAT在HCC中的高表达是由于其被c-Myc/KDM 1A复合物扩增和转录激活。GNPAT补偿c-Myc缺失的HCC细胞中的致癌表型。从机制上讲，GNPAT招募了USP 30酶，该酶去泛素化并稳定动力蛋白相关蛋白1（DRP 1），从而促进线粒体形态，脂质代谢和肝癌发生的调节。抑制GNPAT和DRP 1显著减弱脂质代谢和肝癌发生。此外，DRP 1介导由GNPAT驱动的致癌表型。两者合计，这些结果表明，GNPAT和USP 30介导的DRP 1的稳定在HCC.Significance的发展中起着至关重要的作用：本研究确定并建立了酶GNPAT在肝癌进展中的作用，这可能是一个潜在的肝癌治疗靶点。(C)2018年AACR。
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and the underlying pathophysiology of HCC is highly complex. In this study, we report that, in a bioinformatic screen of 2,783 genes encoding metabolic enzymes, GNPAT, which encodes the enzyme glyceronephosphate O-acyltransferase, is amplified, upregulated, and highly correlated with poor clinical outcome in human patients with HCC. High GNPAT expression in HCC was due to its amplification and transcriptional activation by the c-Myc/KDM1A complex. GNPAT compensated the oncogenic phenotypes in c-Myc-depleted HCC cells. Mechanistically, GNPAT recruited the enzyme USP30, which deubiquitylated and stabilized dynamin-related protein 1 (DRP1), thereby facilitating regulation of mitochondrial morphology, lipid metabolism, and hepatocarcinogenesis. Inhibition of GNPAT and DRP1 dramatically attenuated lipid metabolism and hepatocarcinogenesis. Furthermore, DRP1 mediated the oncogenic phenotypes driven by GNPAT. Taken together, these results indicate that GNPAT and USP30-mediated stabilization of DRP1 play a critical role in the development of HCC.Significance: This study identifies and establishes the role of the enzyme GNPAT in liver cancer progression, which may serve as a potential therapeutic target for liver cancer. (C) 2018 AACR.