Increased fatty acid synthesis is required to meet the demand for membrane expansion of rapidly growing cells. ATP-citrate lyase (ACLY) is upregulated or activated in several types of cancer, and inhibition of ACLY arrests proliferation of cancer cells. Here we show that ACLY is acetylated at lysine residues 540, 546, and 554 (3K). Acetylation at these three lysine residues is stimulated by P300/calcium-binding protein (CBP)-associated factor (PCAF) acetyltransferase under high glucose and increases ACLY stability by blocking its ubiquitylation and degradation. Conversely, the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY. Substitution of 3K abolishes ACLY ubiquitylation and promotes de novo lipid synthesis, cell proliferation, and tumor growth. Importantly, 3K acetylation of ACLY is increased in human lung cancers. Our study reveals a crosstalk between acetylation and ubiquitylation by competing for the same lysine residues in the regulation of fatty acid synthesis and cell growth in response to glucose.

译文

:需要增加脂肪酸的合成才能满足快速生长的细胞膜扩张的需求。 ATP柠檬酸裂合酶(ACLY)在几种类型的癌症中被上调或激活,对ACLY的抑制会阻止癌细胞的增殖。在这里,我们显示ACLY在赖氨酸残基540、546和554(3K)处被乙酰化。在高葡萄糖下,这三个赖氨酸残基的乙酰化受到P300 /钙结合蛋白(CBP)相关因子(PCAF)乙酰转移酶的刺激,并通过阻止其泛素化和降解来提高ACLY稳定性。相反,蛋白质脱乙酰基酶Sirtuin 2(SIRT2)会脱乙酰基并使ACLY不稳定。 3K取代消除了ACLY泛素化并促进了从头脂质合成,细胞增殖和肿瘤生长。重要的是,人类肺癌中ACLY的3K乙酰化增加。我们的研究揭示了乙酰化和泛素化之间的串扰,它们通过竞争相同的赖氨酸残基来调节脂肪酸合成和细胞对葡萄糖的反应。

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