A novel epigenetic target for the treatment of castration-resistant prostate cancer discovered at IOR
Institute of Oncology Research
Researchers from the Prostate Cancer Biology Laboratory, directed by Giuseppina Carbone, M.D., at the Institute of Oncology Research in Bellinzona, have found that an enzyme involved in the cell metabolism has a critical role in the development of treatment-refractory prostate cancers. This study, published in Nature Communications, identifies a novel actionable target for the treatment of patients with prostate cancer.
Castration-resistant prostate cancer is a frequently occurring disease with adverse clinical outcomes and limited therapeutic options. The group has discovered that the enzyme called methionine adenosyl transferase 2a (MAT2A) is the main responsible for the supply of methyl groups to the epigenetic enzymes that control the state of the chromatin in the nucleus of treatment-resistant prostate cancer cells. They found that MAT2A is increased in advanced castration-resistant prostate cancers and is a critical driver of the androgen-indifferent and treatment-refractory state of these tumors.
The team implemented several models of prostate cancer progression along with multiple genomic and proteomic approaches to investigate the role of MAT2A on the epigenetic, transcriptional, and phenotypic reprogramming of prostate cancer cells toward castration resistance. They observed that MAT2A promoted the expression of pro-tumorigenic and stem cell-related genes while repressing canonical androgen-responsive and pro-differentiation genes. Moreover, the genetic and pharmacological inhibition of MAT2A reversed these epigenetic and phenotypic changes. Dr. Carbone explains, “It was striking to observe such profound changes in the chromatin state and the selective modification of histone marks followed by the transition to a normal-like state and increased responsiveness to anticancer therapies”.
These data are consistent with the hypothesis that MAT2A drives dedifferentiation and phenotypic transitions in tumor cells and provide the first proof-of-concept evidence for testing MAT2A inhibitors in prostate cancer patients to overcome treatment resistance and improve clinical outcomes. Dr. Carbone concluded, “Considering that MAT2A inhibitors are already available for clinical use for other diseases, we are very excited about this discovery that opens new opportunities to treat patients with unmanageable prostate cancer”.
Publication: Epigenome-wide impact of MAT2A sustains the androgen-indifferent state and confers synthetic vulnerability in ERG fusion-positive prostate cancer.
DOI 10.1038/s41467-024-50908-7
Summary
Castration-resistant prostate cancer (CRPC) is a frequently occurring disease with adverse clinical outcomes and limited therapeutic options. Here, we identify methionine adenosyl transferase 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 posttranslational 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.
