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Mammalian SIRT6 Represses Invasive Cancer Cell Phenotypes through ATP Citrate Lyase (ACLY)-Dependent Histone
Wei Zheng1,2, Luisa Tasselli1,2, Tie-Mei Li1,2
1Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA 94305, USA.
Genes
|September 28, 2021
Summary
SIRT6 protein controls nuclear ACLY levels, impacting cancer cell adhesion and migration. Inactivation of SIRT6 increases nuclear acetyl-CoA, promoting tumor invasiveness and gene expression.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Biology
Background:
- Dynamic histone acetylation, regulated by HATs and HDACs, is crucial for gene expression.
- SIRT6, a Class III HDAC, regulates chromatin silencing and tumor suppressive genes.
- ATP citrate lyase (ACLY) produces acetyl-CoA for histone acetylation, functioning in both cytoplasm and nucleus.
Purpose of the Study:
- To investigate the novel function of SIRT6 in regulating nuclear ACLY levels.
- To elucidate the role of SIRT6 in ACLY-dependent gene regulation in cancer cells.
- To identify downstream targets of SIRT6 in controlling cancer cell phenotypes.
Main Methods:
- Investigated SIRT6's role in controlling nuclear ACLY.
- Assessed the impact of SIRT6 inactivation on nuclear acetyl-CoA pools.
- Analyzed locus-specific histone acetylation and gene expression in cancer cells.
Main Results:
- SIRT6 inactivation leads to accumulation of nuclear ACLY protein.
- Loss of SIRT6 increases nuclear acetyl-CoA, promoting histone acetylation.
- This drives expression of genes involved in cancer cell adhesion and migration, enhancing invasiveness.
Conclusions:
- SIRT6 suppresses invasive cancer cell phenotypes through a novel mechanism.
- SIRT6 controls nuclear ACLY levels and subsequent gene expression.
- Acetyl-CoA responsive cell migration and adhesion genes are downstream targets of SIRT6.
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