Targeting EMSY-mediated methionine metabolism is a potential therapeutic strategy for triple-negative breast cancer

Treatment of triple-negative breast cancer (TNBC) remains challenging. Cancer stem cells (CSCs) are the most intractable subpopulation of TNBC cells, which has associated with a high risk of relapse and poor prognosis. However, eradication of CSCs continues to be difficult. Here, we integrated the multiomics data of our large TNBC cohort (n=360) to identify vital markers of CSCs. We discovered that EMSY, inducing a BRCAness phenotype, was preferentially expressed in breast CSCs, promoted the enrichment of ALDH+ cells and was positively correlated with poor relapse-free survival. Mechanistically, EMSY competitively bound to the Jmjc domain, which was critical for the enzyme activity of the KDM5B-specific H3K4 demethylase to reshape methionine metabolism and promote CSC self-renewal and tumorigenesis in an H3K4 methylation-dependent manner. Moreover, EMSY accumulation in TNBC cells sensitized them to PARP inhibitors against bulk cells and methionine deprivation against CSCs. These findings indicate that clinically relevant eradication of CSCs could be achieved with a strategy that targets CSC-specific vulnerabilities in amino acid metabolism.