ARID1A-driven modulation of EZH2 impedes proliferation and enhances senescence in breast cancer cells

Abstract

ARID1A mutations, in association with EZH2 overexpression, are linked to various malignancies, particularly those driven by epigenetic dysregulation and associated with therapy resistance. The prevalence of ARID1A mutations is high in ER+ breast cancer, and studies have mainly explored the synthetic lethal effects of these proteins. However, the tumor-suppressive mechanisms of ARID1A are complex and not yet fully understood. In this study, we explored the potential tumor-specific epigenetic antagonism between ARID1A and EZH2 in breast cancer cells, particularly focusing on the modulation of EZH2 by ARID1A through senescence pathway activation. Treatment with DNA-damaging agents induced senescence, which was associated with upregulation of ARID1A expression and a concurrent reduction in EZH2 levels, suggesting a potential role for ARID1A in the induction and maintenance of the senescence phenotype. Overexpression of ARID1A led to reduced EZH2 levels, suppressed cell proliferation in MCF-7 and MDA-MB231 cells, and induced a senescence-like phenotype. These cells exhibited changes in cell-to-cell adhesion, increased filopodium formation, and G0/G1 cell cycle arrest. This antiproliferative effect of ARID1A is mediated through the activation of the p53-p21/p16 axis. Furthermore, ARID1A knockdown-associated downregulation of EZH2 highlights the integral role of ARID1A in destabilizing the expression of EZH2 and contributing to cell cycle arrest. Importantly, we found that dasatinib treatment selectively targeted tumor cells overexpressing ARID1A. These findings provide preliminary insight into the molecular mechanisms by which ARID1A regulates EZH2 and establishes a senescence phenotype, offering valuable directions for developing more effective and personalized treatments.