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Doctoral thesis

Methionine adenosyltransferase 2a (MAT2A) is an actionable therapeutic target in androgen-indifferent prostate tumors

  • 2024

PhD: Università della Svizzera italiana

English Prostate cancer (PCa) is a major health problem and a leading cause of cancer death in Western countries. Castration resistant prostate cancer (CRPC) presents an adverse clinical outcome, characterized by an androgen indifferent state and poor response to therapy. In this work, we identify a novel role for methionine adenosyltransferase 2a (MAT2A) as a driver of CRPC. We show that MAT2A is up regulated in CRPC, and that it cooperates with ERG in the promotion of cell plasticity, stemness and tumorigenic properties. We integrated multiple omics techniques to study the broad impact of MAT2A on the transcriptional and epigenetic landscape of ERG positive PCa models. Mechanistically, MAT2A enhances the deposition of H3K4me2 at multiple genomic sties, thereby promoting the expression of a pro tumorigenic and non canonical AR transcriptional network in CRPC models. Genetic ablation and pharmacological inhibition of MAT2A reversed this epigenetic and transcriptional remodeling, eventually improving the response to AR and EZH2 inhibitors. This work highlights a novel function of MAT2A in the epigenetic reprogramming of PCa, and points to a synthetic vulnerability of ERG positive CRPC to MAT2A inhibitors.
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