Dual inhibition of PRMT1 and SUV39H1 suppresses breast cancer progression and enhances immunotherapy response

Protein arginine methyltransferase 1 (PRMT1) dysregulation is frequently observed in various human cancers, including breast cancer. However, the antitumor efficacy of PRMT1 inhibitors remains limited in the treatment of breast cancer. Here, we propose a dual epigenetic inhibition strategy that effectively suppresses breast cancer growth and metastasis. We demonstrate that GSK3368715, a small-molecule inhibitor of PRMT1, downregulates the protein levels of the histone lysine methyltransferase SUV39H1 by enhancing its ubiquitination. Dual inhibition of PRMT1 and SUV39H1 results in significantly greater suppression of tumor growth and metastasis compared to either monotherapy, supporting the synergistic effects of targeting two epigenetic regulators. Consistently, dual inhibition markedly suppresses the growth of breast cancer organoids relative to single-agent treatments. Mechanistically, co-inhibition of SUV39H1 and PRMT1 enhances chromatin accessibility in promoter regions, thereby promoting the expression of key regulators involved in cell growth and migration. Furthermore, dual inhibition increases infiltration of CD8+ T cells and NK cells and upregulates PD-L1 expression. Importantly, the combination of dual inhibition with anti-PD-L1 antibody enhances the responsiveness of breast cancer to immunotherapy. Taken together, our findings indicate that co-targeting PRMT1 and SUV39H1 represents a promising therapeutic strategy for breast cancer.