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Acetate Triggers Epigenetic Activation of Cell Cycle Arrest via ACSS2-H2A.Zac Axis in Esophageal Squamous Cell Carcinoma [ChIP-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309713 | GEO | 2025/10/06

REPOSITORIES: GEO

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Project description:Background and Aims: Many inflammatory diseases are associated with microbial dysbiosis, which may considerably alter the production of short-chain fatty acids (SCFAs). SCFAs are produced in the large bowel through bacterial fermentation of dietary fiber and play an important role in maintaining gut homeostasis. SCFAs, particularly acetate and butyrate, show beneficial immunomodulatory effects contributing to the prevention of inflammatory and allergic reactions. Thus, reduced production of SCFAs may impact on the mucosal immune responses critical to fighting pathogens. This study aims to determine the influence of SCFAs on a murine model of colonic bacterial infection. Methods: In the present study, we used acetate- (HAMSA) or butyrate- (HAMSB) yielding diets to deliver high concentrations of individual SCFAs to the large bowel of mice infected with C. rodentium. We assessed the effects of these SCFAs on clinical burden and gut pathogenicity in correlation with changes in bacteria growth, fecal microbiota composition, function and changes in the immunological profile. Results: Here we show in vitro that acetate and butyrate directly inhibited growth of the attaching and effacing (A/E) pathogen C. rodentium in a bacteriostatic manner. This correlated with reduced expression of Tir, a gene responsible for bacterial adherence and pathogenicity. Interestingly, HAMSA-fed mice presented reduced clinical scores during C. rodentium infection associated with high concentrations of fecal acetate. This was linked with compositional and functional changes in the microbiota when examining 16s sequencing and proteomics analysis. The HAMSA mediated is protection involved increased expression IL-22 and Muc-2 in the colon and increased numbers of CD8αα+ TCRγδ T cells in the colonic epithelium. These effects were dependent on GPR43, a metabolite-sensing GPCR that binds acetate. Conclusions: We established a promising new approach to moderate bacterial gut infections by manipulating the gut microbiota and mucosal immune tolerance through diets that yield the SCFA acetate.

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Acetate Triggers Epigenetic Activation of Cell Cycle Arrest via ACSS2-H2A.Zac Axis in Esophageal Squamous Cell Carcinoma [ChIP-seq]

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