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

ABSTRACT: Castration-resistant prostate cancer (CRPC) is a frequently occurring disease with adverse clinical outcomes and limited therapeutic options. Here, we identify a novel role of methionine adenosyltransferase 2a (MAT2A) as a driver of the androgen-indifferent state in ERG fusion-positive CRPC. We show that MAT2A is upregulated in CRPC and cooperates with ERG in promoting cell plasticity, stemness and tumorigenesis. RNA, ATAC and ChIP sequencing coupled with mass spectrometry analysis of histone post-translational modifications 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 in CRPC models. Genetic and pharmacological inhibition of MAT2A in preclinical models reversed this transcriptional and epigenetic remodeling, promoting luminal differentiation and improving the response to AR and EZH2 inhibitors. This data reveals a previously unrecognized function of MAT2A in epigenetic reprogramming and a synthetic vulnerability to MAT2A inhibitors in ERG fusion-positive CRPC.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Prostate Cancer Cell Line

SUBMITTER: Matteo Pecoraro

LAB HEAD: Giuseppina M. Carbone

PROVIDER: PXD042895 | Pride | 2024-06-06

REPOSITORIES: Pride

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			Action	DRS
	20220914_MP069_AlCa_SA_VCaP_shCTRL_1.raw	Raw
	20220914_MP069_AlCa_SA_VCaP_shCTRL_2.raw	Raw
	20220914_MP069_AlCa_SA_VCaP_shCTRL_3.raw	Raw
	20220914_MP069_AlCa_SA_VCaP_shMAT2A_1.raw	Raw
	20220914_MP069_AlCa_SA_VCaP_shMAT2A_2.raw	Raw

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