A histone-centric multi-omics study shows that increased H3K4 methylation sustains triple-negative breast cancer phenotypes.

Altered histone post-translational modifications are frequently associated with cancer. Here, we apply mass-spectrometry to study the epigenetic landscapes of breast cancer subtypes, with a particular focus on triple-negative breast cancers (TNBCs), a heterogeneous group lacking well-defined molecular targets and effective therapies. The analysis of over 200 tumors reveals epigenetic signatures that discriminate TNBCs from the other BC subtypes, and that distinguish TNBC patients with different prognoses. Employing a multi-OMICs approach integrating epigenomics, transcriptomics, and proteomics data, we investigate the mechanistic role of increased H3K4 methylation in TNBCs, demonstrating that H3K4me2 sustains the expression of genes associated with the TNBC phenotype. Through CRISPR-mediated editing, we establish a causal relationship between H3K4me2 and gene expression for several targets. Furthermore, treatment with H3K4 methyltransferase inhibitors reduce TNBC cell growth in vitro and in vivo. Collectively, our results unravel a novel epigenetic pathway implicated in TNBC pathogenesis and suggest new opportunities for targeted therapy.