Epigenome-wide impact of MAT2A sustains the androgen-indifferent state and confers synthetic vulnerability in ERG fusion-positive prostate cancer

Alessia Cacciatore, Dheeraj Shinde, Carola Musumeci, Giada Sandrini, Luca Guarrera, Domenico Albino, Gianluca Civenni, Elisa Storelli, Simone Mosole, Elisa Federici, Alessio Fusina, Marta Iozzo, Andrea Rinaldi, Matteo Pecoraro, Roger Geiger, Marco Bolis, Carlo V. Catapano and Giuseppina M. Carbone ()
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Alessia Cacciatore: Università della Svizzera Italiana (USI)
Dheeraj Shinde: Università della Svizzera Italiana (USI)
Carola Musumeci: Università della Svizzera Italiana (USI)
Giada Sandrini: Università della Svizzera Italiana (USI)
Luca Guarrera: Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS
Domenico Albino: Università della Svizzera Italiana (USI)
Gianluca Civenni: Università della Svizzera Italiana (USI)
Elisa Storelli: Università della Svizzera Italiana (USI)
Simone Mosole: Università della Svizzera Italiana (USI)
Elisa Federici: Università della Svizzera Italiana (USI)
Alessio Fusina: Università della Svizzera Italiana (USI)
Marta Iozzo: Università della Svizzera Italiana (USI)
Andrea Rinaldi: Università della Svizzera Italiana (USI)
Matteo Pecoraro: Università della Svizzera Italiana (USI)
Roger Geiger: Università della Svizzera Italiana (USI)
Marco Bolis: Università della Svizzera Italiana (USI)
Carlo V. Catapano: Università della Svizzera Italiana (USI)
Giuseppina M. Carbone: Università della Svizzera Italiana (USI)

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: Abstract Castration-resistant prostate cancer (CRPC) is a frequently occurring disease with adverse clinical outcomes and limited therapeutic options. Here, we identify methionine adenosyltransferase 2a (MAT2A) as a critical driver of the androgen-indifferent state in ERG fusion-positive CRPC. MAT2A is upregulated in CRPC and cooperates with ERG in promoting cell plasticity, stemness and tumorigenesis. RNA, ATAC and ChIP-sequencing coupled with histone post-translational modification analysis by mass spectrometry show that MAT2A broadly impacts the transcriptional and epigenetic landscape. MAT2A enhances H3K4me2 at multiple genomic sites, promoting the expression of pro-tumorigenic non-canonical AR target genes. Genetic and pharmacological inhibition of MAT2A reverses the transcriptional and epigenetic remodeling in CRPC models and improves the response to AR and EZH2 inhibitors. These data reveal a role of MAT2A in epigenetic reprogramming and provide a proof of concept for testing MAT2A inhibitors in CRPC patients to improve clinical responses and prevent treatment resistance.

Date: 2024
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DOI: 10.1038/s41467-024-50908-7

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