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

Roberta Noberini (), Giulia Robusti, Alessandro Vai, Evelyn Oliva Savoia, Maria Giovanna Jodice, Giovanni Bertalot, Betül Çat, Isabella Pallavicini, Giuseppina Bonizzi, Maria Capra, Claudia Anna Sangalli, Federico Zambelli, Nicola Fusco, Salvatore Pece, Giulio Pavesi, Saverio Minucci and Tiziana Bonaldi ()
Additional contact information
Roberta Noberini: IEO European Institute of Oncology IRCSS
Giulia Robusti: IEO European Institute of Oncology IRCSS
Alessandro Vai: IEO European Institute of Oncology IRCSS
Evelyn Oliva Savoia: IEO European Institute of Oncology IRCSS
Maria Giovanna Jodice: IEO European Institute of Oncology IRCSS
Giovanni Bertalot: IEO European Institute of Oncology IRCSS
Betül Çat: IEO European Institute of Oncology IRCSS
Isabella Pallavicini: IEO European Institute of Oncology IRCSS
Giuseppina Bonizzi: IEO European Institute of Oncology IRCCS
Maria Capra: IEO European Institute of Oncology IRCCS
Claudia Anna Sangalli: IEO European Institute of Oncology IRCSS
Federico Zambelli: Università degli Studi di Milano
Nicola Fusco: IEO European Institute of Oncology IRCCS
Salvatore Pece: IEO European Institute of Oncology IRCSS
Giulio Pavesi: Università degli Studi di Milano
Saverio Minucci: IEO European Institute of Oncology IRCSS
Tiziana Bonaldi: IEO European Institute of Oncology IRCSS

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63745-z

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