Targeting ACSS2 activity suspends the formation of chemoresistance through suppressed histone H3 acetylation in human breast cancer

Histone hyperacetylation is a prevalent occurrence in neoplastic cells within tumors, arising from the coordinated interplay of various biological processes. This phenomenon relies on the robust modulation of gene expression to effectively adapt to environmental adaptations in response to spatial and temporal fluctuations. Histone hyperacetylation has been closely linked to the proliferation, metastasis, and therapeutic resistance of tumor cells. In this investigation, we substantiated the overexpression of the well-documented acetyl-CoA synthetase short-chain family member 2 (ACSS2) at both protein and mRNA levels in breast cancer (BC) cells derived from tumor tissues. Subsequent examinations unveiled that the heightened acetylation of histone H3 in BC cells under environmental stress is contingent upon the accumulation of ACSS2 and enhanced acetyl-CoA synthesis. Intriguingly, the augmentation of H3K9 and H3K27 acetylation (H3K9/K27ac) induced by nutrient stress, mediated by ACSS2, was primarily governed by the histone acetyltransferases (HATs) CBP/p300, with no significant association with conventional histone deacetylases (HDACs). Supplementation with an alternative carbon source, acetate, confirmed that targeted inhibition of ACSS2 mitigated the further elevation of ATP-binding cassette (ABC) transporters, specifically ABC subfamily B member 1 (ABCB1/MDR1) and breast cancer resistance protein (BCRP/ABCG2). These transporters reportedly play crucial roles in both energy metabolic homeostasis and the modulation of intracellular drug concentrations, driven by histone H3 hyperacetylation. Mechanistically, inhibitors of ACSS2 significantly mitigated the resistance of BC cells to doxorubicin and cisplatin, predominantly by reducing H3K27ac levels through the downregulation of nuclear acetyl-CoA content and constraining its binding to the promoters of MDR1 and BCRP. The poor overall survival of BC patients associated with high ACSS2 expression and its positive correlation with MDR1 and BCRP were further confirmed in human BC tumors. Consequently, histone acetylation induced by ACSS2 emerges as a promising epigenetic target for the treatment of BC.