Acetyl-CoA Synthetase 2 Promotes Acetate Utilization and Maintains Cancer Cell Growth under Metabolic Stress

TLDR

Cancer cells use acetate as a nutritional source via ACSS2, contributing a substantial fraction of carbon to fatty acids and phospholipids. ACSS2 is upregulated in hypoxic, lipid‑depleted tumors, correlates with stage and survival, and its silencing impairs xenograft growth. A graphical abstract summarizes the study.

Abstract

Highlights•ACSS2 expression positively correlates with tumor stage and patient survival•Hypoxia and low lipid availability synergistically stimulate ACSS2 expression•Acetate is a major source of carbon for lipid synthesis during metabolic stress•ACSS2 is required for growth of tumor xenografts harboring ACSS2 copy-number gainsSummaryA functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment. Graphical abstract