Mammalian SIRT6 Represses Invasive Cancer Cell Phenotypes through ATP Citrate Lyase (ACLY)-Dependent Histone Acetylation

Abstract

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.

ARHGEF3 regulates the stability of ACLY to promote the proliferation of lung cancer

“…Previous studies demonstrated that ACLY protein homeostasis was regulated by acetylation [ 20 , 21 ]. We wondered whether ARHGEF3 affected ACLY protein stability via regulating acetylation.…”

SIRT2‐mediated deacetylation of ACLY promotes the progression of oesophageal squamous cell carcinoma

“…The interaction between ACLY and SIRT2 in ESCC cells was further confirmed. Although SIRT2 may be an important deacetylase for regulating the level of ACLY acetylation in ESCC cells, current reports about other sirtuin protein families, such as SIRT6, also regulate the level of ACLY acetylation 49 . However, whether SIRT6 or other sirtuin families such as SIRT1, SIRT3, etc.…”

“…Although SIRT2 may be an important deacetylase for regulating the level of ACLY acetylation in ESCC cells, current reports about other sirtuin protein families, such as SIRT6, also regulate the level of ACLY acetylation. 49 However, whether SIRT6 or other sirtuin families such as SIRT1, in mouse liver cell line AML12, while SIRT2 promotes the deacetylation of ACLY-3K, resulting in the reduction of ACLY stability. 50 In the present study, BMS-303141 inhibited the expression of SIRT2, and AGK2 also down-regulated the expression of ACLY.…”

Deletion of ACLY Disrupts Histone Acetylation and IL-10 Secretion in Trophoblasts, Which Inhibits M2 Polarization of Macrophages: A Possible Role in Recurrent Spontaneous Abortion

“…Acetyl CoA is a key metabolic intermediate connecting metabolism, signal transduction, and epigenetics. It is an acetyl donor for protein acetylation reactions and plays an important role in chromatin dynamics and gene regulation [ 30 , 31 ]. Many studies have established a close relationship between epigenetic regulation and placental trophoblast function by proving the key role of epigenetic regulatory factors in maintaining a healthy pregnancy [ 32 , 33 ].…”