Increasing <scp>RB1</scp> Expression by Targeting <scp>EZH2</scp> in Triple‐Negative Breast Cancer

Loss of RB1 function represents a defining characteristic of triple-negative breast cancer (TNBC) and is intricately associated with resistance to therapeutic interventions. In this study, we investigate the epigenetic mechanisms governing RB1 expression in TNBC. Employing a combination of bioinformatics analyses and experimental validations, we identified lysine histone methyltransferase EZH2 as a key upstream regulator of RB1 expression. EZH2 primarily mediates trimethylation of lysine 27 on histone H3 as the catalytic subunit of the Polycomb repressive complex 2 (PRC2) complex. Furthermore, our findings demonstrate that pharmacological inhibition of EZH2 leads to a significant upregulation of RB1 expression levels, mediated by enhanced enrichment of the activating histone marker H3K27ac at the RB1 enhancer region, as evidenced by ATAC-sequencing and ChIP-qPCR assays. These insights unveil a promising clinical avenue for combating RB1-mediated drug resistance in TNBC through the strategic integration of epigenetic-targeting agents.