Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2) is Required for Colorectal Cancer Progression and Serves as a Druggable Target for Colorectal Cancer Treatment

Acyl-CoA synthetase short chain family member 2 (ACSS2) catalyzes the conversion of acetate to acetyl-CoA, a key metabolite required for de novo lipogenesis and protein acetylation. Here we show that ACSS2 expression is markedly elevated at all stages of human colorectal cancer (CRC), and Acss2 silencing or conditional genetic ablation leads to a marked reduction in CRC tumor loads in mouse tumor xenograft models and CRC models induced by colonic epithelial Apc mutation or azoxymethane (AOM)/dextran sodium sulfate (DSS) treatment. Tumors with ACSS2 depletion exhibit robust DNA damage and excessive apoptosis, leading to increased recruitment of macrophages and CD8+ T cells to the tumor microenvironment. Further studies confirm that ACSS2 promotes CRC growth by blocking DNA damage and apoptosis under nutritional stress commonly occurring in solid tumors, suggesting ACSS2 is a therapeutic target for CRC therapy. Indeed, treatment with a small molecule ACSS2 inhibitor (ACSS2i) markedly suppresses tumor growth in CRC xenograft models and Apc-mutation induced sporadic CRC models. Consistently, ACSS2i treatment increases DNA damage and induces apoptosis in the tumors. These observations indicate that the conversion of acetate to acetyl-CoA by ACSS2 is crucial for CRC progression, and ACSS2 is a druggable target for CRC management.