Acetyl-CoA Synthetase 2 Confers a Growth Advantage under Metabolic Stress

Deregulated expression of enzymes involved in fatty acid biosynthesis, such as fatty acid synthase (FASN), and activation of de novo lipogenesis commonly occur in many cancers and contribute to tumor growth and metastasis. However, targeting FASN has proven difficult due to toxicity, demonstrating the need to identify other therapeutic targets to suppress lipid metabolism. Schug and colleagues performed a functional genomics screen in a panel of breast and prostate cancer cell lines under hypoxic or low-serum conditions, which were shown to recapitulate the sensitivity to FASN inhibition observed in tumors in vivo and to render cells dependent on de novo lipogenesis via reprogramming of lipid metabolism. This screen identified acetyl-CoA synthetase 2 (ACSS2), which ligates acetate with coenzyme A (CoA) to generate acetyl-CoA, as required for the survival of cancer cells challenged with metabolic stress. ACSS2 was upregulated in invasive ductal carcinomas and exhibited copy-number gain in breast tumors, and its expression correlated with breast cancer progression and prostate cancer metastasis. Mechanistically, hypoxia and low serum synergistically induced ACSS2 expression via sterol regulatory element–binding transcription factor 2 and, to a lesser extent, hypoxia-inducible factor, which paralleled the regulation of FASN expression under metabolic stress. Importantly, exposure to metabolic stress increased acetate uptake and its incorporation into acetyl-CoA and enhanced the synthesis of fatty acids and membrane phospholipids from acetate-derived acetyl-CoA. Depletion of ACSS2 decreased acetate consumption and impaired de novo lipogenesis, similar to the effects of FASN inhibition. Furthermore, elevated ACSS2 expression was observed in hypoxic tumor regions, and silencing of ACSS2 suppressed the growth of spheroids and xenograft tumors. In sum, these data identify acetate as a key regulator of cancer cell growth within the metabolically stressed tumor microenvironment, and suggest ACSS2 as a potential therapeutic target.

Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 2015;27:57–71.