Besides the conventional carbon sources, acetyl-CoA has recently been shown to be generated from acetate in various types of cancers, where it promotes lipid synthesis and tumour growth. The underlying mechanism, however, remains largely unknown. We find that acetate induces a hyperacetylated state of histone H3 in hypoxic cells. Acetate predominately activates lipogenic genes ACACA and FASN expression by increasing H3K9, H3K27 and H3K56 acetylation levels at their promoter regions, thus enhancing de novo lipid synthesis, which combines with its function as the metabolic precursor for fatty acid synthesis. Acetyl-CoA synthetases (ACSS1, ACSS2) are involved in this acetate-mediated epigenetic regulation. More importantly, human hepatocellular carcinoma with high ACSS1/2 expression exhibit increased histone H3 acetylation and FASN expression. Taken together, this study demonstrates that acetate, in addition to its ability to induce fatty acid synthesis as an immediate metabolic precursor, also functions as an epigenetic metabolite to promote cancer cell survival under hypoxic stress.

中文翻译：

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乙酸盐是一种表观遗传代谢产物，可在缺氧条件下促进脂质合成。

除了传统的碳源，最近还显示乙酰辅酶A是由乙酸盐在各种类型的癌症中产生的，可促进脂质合成和肿瘤生长。但是，其基本机制仍然未知。我们发现乙酸盐在低氧细胞中诱导组蛋白H3的超乙酰化状态。乙酸主要通过增加启动子区域的H3K9，H3K27和H3K56乙酰化水平来激活脂肪生成基因ACACA和FASN的表达，从而增强从头脂质合成，并结合其作为脂肪酸合成的代谢前体的功能。乙酰辅酶A合成酶（ACSS1，ACSS2）参与这种乙酸盐介导的表观遗传调控。更重要的是，具有高ACSS1 / 2表达的人肝细胞癌表现出增加的组蛋白H3乙酰化和FASN表达。