Acetate suppresses tumorigenesis through ACSS2-dependent H2A.Z acetylation in esophageal squamous cell carcinoma.

Deciphering the epigenome-metabolome crosstalk during tumorigenesis is critical for therapeutic strategies. While the epigenetic oncogenic paradigm of acetate and its converter ACSS2 has been well established in multiple cancers, their roles in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we identify significantly decreased acetate levels and ACSS2 expression in human ESCC tissues, with low ACSS2 linked to poor prognosis. Exogenous acetate supplementation robustly inhibits ESCC proliferation in vitro and in vivo. Mechanistically, acetate is utilized by ACSS2 to promote H2A.Z acetylation, which transcriptionally activates ACSS2 itself and ATM, a DNA damage response regulator downregulated in ESCC and whose ectopic overexpression inhibits cell proliferation. Either mutating the three H2A.Z acetylation sites from lysine to arginine or ACSS2 knockdown abrogates acetate effects, suggesting a potential positive feedback loop. Our work defines an acetate-ACSS2-H2A.Zac-ATM tumor-suppressive axis in ESCC, pointing to a compelling therapeutic strategy by targeting the epigenetic regulator H2A.Z.