Acetyl-CoA synthetase short-chain family member 2 (ACSS2)

Acetyl-CoA synthetase short-chain family member 2 (ACSS2) is a cytosolic and nuclear enzyme that catalyzes the ATP-dependent conversion of acetate to acetyl-CoA, primarily supporting lipid synthesis, energy production, and acetylation processes in mammalian cells. It acts as a monomer, with expression regulated by sterol regulatory element-binding proteins (SREBPs) that respond to cholesterol and fatty acid levels, and it produces crotonyl-CoA for histone crotonylation. ACSS2 is highly expressed in liver, kidney, and heart, and under metabolic stress like nutrient deprivation or hypoxia, it translocates to the nucleus via AMPK phosphorylation at Ser659, where it interacts with transcription factors such as TFEB to promote histone acetylation, autophagy, and lysosomal biogenesis. In cancer cells, including hepatocellular carcinoma, glioblastoma, and lung tumors, upregulated ACSS2 enables acetate utilization for acetyl-CoA homeostasis, enhancing proliferation, invasion, metastasis, and survival in nutrient-poor or hypoxic tumor microenvironments. This role in metabolic reprogramming positions ACSS2 as an emerging therapeutic target in oncology, though no approved drugs are known.

Other names

Acyl-CoA synthetase short chain family member 2ACSA