The modulation of dynamic histone acetylation states is key for organizing chromatin structure and modulating gene expression and is regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes. The mammalian SIRT6 protein, a member of the Class III HDAC Sirtuin family of NAD+-dependent enzymes, plays pivotal roles in aging, metabolism, and cancer biology. Through its site-specific histone deacetylation activity, SIRT6 promotes chromatin silencing and transcriptional regulation of aging-associated, metabolic, and tumor suppressive gene expression programs. ATP citrate lyase (ACLY) is a nucleo-cytoplasmic enzyme that produces acetyl coenzyme A (acetyl-CoA), which is the required acetyl donor for lysine acetylation by HATs. In addition to playing a central role in generating cytosolic acetyl-CoA for de novo lipogenesis, a growing body of work indicates that ACLY also functions in the nucleus where it contributes to the nutrient-sensitive regulation of nuclear acetyl-CoA availability for histone acetylation in cancer cells. In this study, we have identified a novel function of SIRT6 in controlling nuclear levels of ACLY and ACLY-dependent tumor suppressive gene regulation. The inactivation of SIRT6 in cancer cells leads to the accumulation of nuclear ACLY protein and increases nuclear acetyl-CoA pools, which in turn drive locus-specific histone acetylation and the expression of cancer cell adhesion and migration genes that promote tumor invasiveness. Our findings uncover a novel mechanism of SIRT6 in suppressing invasive cancer cell phenotypes and identify acetyl-CoA responsive cell migration and adhesion genes as downstream targets of SIRT6.

中文翻译：

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哺乳动物 SIRT6 通过 ATP 柠檬酸裂解酶 (ACLY) 依赖性组蛋白乙酰化抑制侵袭性癌细胞表型

动态组蛋白乙酰化状态的调节是组织染色质结构和调节基因表达的关键，并受到组蛋白乙酰转移酶 (HAT) 和组蛋白脱乙酰酶 (HDAC) 的调节。哺乳动物 SIRT6 蛋白是 NAD+ 依赖性酶的 III 类 HDAC Sirtuin 家族的成员，在衰老、代谢和癌症生物学中发挥着关键作用。通过其位点特异性组蛋白脱乙酰化活性，SIRT6 促进染色质沉默以及衰老相关、代谢和肿瘤抑制基因表达程序的转录调节。ATP 柠檬酸裂解酶 (ACLY) 是一种核胞质酶，可产生乙酰辅酶 A (乙酰辅酶 A)，乙酰辅酶 A 是 HAT 赖氨酸乙酰化所需的乙酰基供体。除了在生成细胞质乙酰辅酶A以促进脂肪从头生成方面发挥核心作用外，越来越多的研究表明，ACLY 也在细胞核中发挥作用，有助于对癌细胞中组蛋白乙酰化的核乙酰辅酶 A 可用性进行营养敏感调节。在这项研究中，我们发现了 SIRT6 在控制 ACLY 和 ACLY 依赖性肿瘤抑制基因调控的核水平方面的新功能。癌细胞中 SIRT6 的失活导致核 ACLY 蛋白的积累并增加核乙酰辅酶 A 库，进而驱动位点特异性组蛋白乙酰化以及促进肿瘤侵袭的癌细胞粘附和迁移基因的表达。我们的研究结果揭示了 SIRT6 抑制侵袭性癌细胞表型的新机制，并将乙酰辅酶 A 响应性细胞迁移和粘附基因确定为 SIRT6 的下游靶标。