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

Zhenhui Chen1, Chenghao Li2, Yunxi Zhang1

  • 1Institute of Genomic Medicine, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325035, P.R. China.

Cell Reports
|August 22, 2026
PubMed

Insights

This study reveals a tumor-suppressive axis in esophageal squamous cell carcinoma (ESCC) involving acetate, ACSS2, and H2A.Z. Supplementing acetate inhibits ESCC growth by activating a key DNA damage pathway.

Area of Science:

  • Oncology
  • Epigenetics
  • Metabolomics

Background:

  • Epigenome-metabolome crosstalk is crucial for cancer development.
  • The roles of acetate and ACSS2 in esophageal squamous cell carcinoma (ESCC) are not well understood.

Purpose of the Study:

  • To investigate the function of acetate and ACSS2 in ESCC.
  • To elucidate the underlying molecular mechanisms of their action.
  • To identify potential therapeutic targets for ESCC.

Main Methods:

  • Analysis of human ESCC tissues for acetate levels and ACSS2 expression.
  • In vitro and in vivo experiments with exogenous acetate supplementation.
  • Investigation of H2A.Z acetylation and its effect on gene expression.
  • ACSS2 knockdown and mutation studies.

Main Results:

  • Decreased acetate levels and ACSS2 expression were observed in ESCC tissues, correlating with poor prognosis.
  • Exogenous acetate significantly inhibited ESCC proliferation.
  • Acetate, via ACSS2, promotes H2A.Z acetylation, activating ACSS2 and ATM (a DNA damage regulator).
  • H2A.Z acetylation sites and ACSS2 are essential for acetate's effects.

Conclusions:

  • A novel acetate-ACSS2-H2A.Zac-ATM tumor-suppressive axis was identified in ESCC.
  • Targeting epigenetic regulator H2A.Z presents a potential therapeutic strategy for ESCC.
Keywords:
ACSS2ATMCP: cancerCP: metabolismESCCH2A.Z acetylationacetatetumor suppression

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