Acetate Triggers Epigenetic Activation of Cell Cycle Arrest via ACSS2-H2A.Zac Axis in Esophageal Squamous Cell Carcinoma [ChIP-seq]
Short-chain fatty acids (SCFAs) are closely associated with cancer, yet their involvement in the progression of esophageal squamous cell carcinoma (ESCC) remains unexplored. Here, we show a significantly decreased transcriptional activity of the SCFA metabolic pathway along with a reduced acetate accumulation in ESCC tissues compared to adjacent normal tissues. Exogenous acetate supplementation significantly suppresses ESCC proliferation both in vitro and in vivo. Mechanistically, acetate promotes the incorporation of the transcriptional active histone modification H2A.Zac into chromatin through ACSS2, an enzyme that converts acetate to acetyl-CoA and is aberrantly downregulated in ESCC. H2A.Zac subsequently activates the transcription of cell cycle arrest regulators like ATM and ACSS2 itself to form a positive feedback loop that facilitates acetate utilization, thereby slowing tumor growth. Either mutating the three H2A.Z acetylation sites from lysine to arginine or ACSS2 knockdown abrogated the anti-tumor effects of acetate. Taken together, our findings reveal a previously unrecognized metabolic-epigenetic regulatory loop orchestrated by acetate-ACSS2-H2A.Zac-ATM axis in ESCC, which offers novel insights for its diagnosis and therapy. Overall design: ChIP-seq of H2AZac and paired RNA-seq were performed in the esophageal squamous cell carcinoma cell line KSE450 before and after acetate treatment.