ACSS2 is required for colorectal cancer progression and a druggable target for colorectal cancer treatment.

Acyl-CoA synthetase short chain family member 2 (ACSS2) catalyzes the conversion of acetate to acetyl-CoA. Here we show that ACSS2 expression is markedly elevated in all stages of human colorectal cancer (CRC), and Acss2 silencing or genetic ablation leads to a marked reduction in CRC tumor load in allograft and xenograft models and CRC models induced by epithelial Apc deletion or azoxymethane/dextran sodium sulfate treatment. Tumors with ACSS2 depletion exhibit robust DNA damage, excessive apoptosis, and increased recruitment of macrophages and CD8+ T cells to the tumor microenvironment. Treatment with a small-molecule ACSS2 inhibitor markedly suppresses tumor growth in allograft/xenograft and Apc-mutant CRC models. ACSS2 promotes tumor cell growth by blocking DNA damage and apoptosis under nutritional stress. Collectively, these data indicate that the conversion of acetate to acetyl-CoA by ACSS2 is required for CRC progression and ACSS2 is a potential druggable target for CRC management.