Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200135, China; Institute of Medical Genetics, Tongji University, Shanghai 200331, China.
Mitochondrion. 2021 Sep;60:150-159. doi: 10.1016/j.mito.2021.08.004. Epub 2021 Aug 8.
As an essential post-translational modification, acetylation participates in various cellular processes and shows aberrances during tumorigenesis. Owing to its modification substrate, acetyl-CoA, acetylation is postulated as a depot for acetyl groups and evolve to build a connection between epigenetics and metabolism. Here we depict a distinct acetylome atlas of hepatocellular carcinoma from the perspectives of both protein acetylation and acetyl-CoA metabolism. We found that tumor acetylome demonstrated a compartment-dependent alteration that the acetylation level of mitochondrial proteins tended to be decreased while nuclear proteins were highly acetylated. In addition, elevated expression of ATP-citrate synthase (ACLY) was observed in tumors, which would facilitate histone acetylation by transporting mitochondrial acetyl coenzyme A to the nucleus. A hypothetical model of the oncogenic acetylome was proposed that growing demands for histone acetylation in tumor cells would drive the relocalization of acetyl-CoA to the nucleus, which may contribute to the global deacetylation of mitochondrial proteins to support the nuclear acetyl-CoA pool in an ACLY-dependent manner. Our findings are thought-provoking on the potential linkage between epigenetics and metabolism in the progression of tumorigenesis.
作为一种重要的翻译后修饰方式，乙酰化参与了多种细胞过程，并在肿瘤发生过程中出现异常。由于其修饰底物乙酰辅酶 A，乙酰化被认为是乙酰基的储存库，并演变为连接表观遗传学和代谢的桥梁。在这里，我们从蛋白质乙酰化和乙酰辅酶 A 代谢的角度描绘了肝癌的独特乙酰组图谱。我们发现肿瘤乙酰组表现出一种与细胞器相关的改变，即线粒体蛋白的乙酰化水平趋于降低，而核蛋白高度乙酰化。此外，我们观察到肿瘤中 ATP-柠檬酸合酶 (ACLY) 的表达升高，这将通过将线粒体乙酰辅酶 A 转运到细胞核来促进组蛋白乙酰化。我们提出了一个癌基因乙酰组的假设模型，即肿瘤细胞中组蛋白乙酰化的增长需求将促使乙酰辅酶 A 向细胞核重新定位，这可能有助于线粒体蛋白的全局去乙酰化，以 ACLY 依赖的方式支持核乙酰辅酶 A 池。我们的发现令人深思，它提示了表观遗传学和代谢在肿瘤发生过程中的潜在联系。
