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组蛋白修饰全基因组范围影响 MAT2A 维持雄激素不敏感状态并赋予 ERG 融合阳性前列腺癌合成脆弱性。

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

机构信息

Institute of Oncology Research (IOR), Università della Svizzera Italiana (USI), 6500, Bellinzona, Switzerland.

Swiss Institute of Bioinformatics, Bioinformatics Core Unit, 6500, Bellinzona, Switzerland.

出版信息

Nat Commun. 2024 Aug 6;15(1):6672. doi: 10.1038/s41467-024-50908-7.

DOI:10.1038/s41467-024-50908-7
PMID:39107274
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11303763/
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.

摘要

去势抵抗性前列腺癌（CRPC）是一种常发生的疾病，具有不良的临床结局和有限的治疗选择。在这里，我们确定蛋氨酸腺苷转移酶 2a（MAT2A）是 ERG 融合阳性 CRPC 中雄激素不敏感状态的关键驱动因素。MAT2A 在 CRPC 中上调，并与 ERG 合作促进细胞可塑性、干性和肿瘤发生。RNA、ATAC 和 ChIP-seq 测序，以及通过质谱进行组蛋白翻译后修饰分析表明，MAT2A 广泛影响转录组和表观遗传景观。MAT2A 在多个基因组位点增强 H3K4me2，促进促肿瘤非经典 AR 靶基因的表达。MAT2A 的遗传和药理学抑制可逆转 CRPC 模型中的转录和表观遗传重塑，并改善对 AR 和 EZH2 抑制剂的反应。这些数据揭示了 MAT2A 在表观遗传重编程中的作用，并为在 CRPC 患者中测试 MAT2A 抑制剂以改善临床反应和预防治疗耐药性提供了概念验证。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/eec9963373a2/41467_2024_50908_Fig9_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/f1127569d86c/41467_2024_50908_Fig4_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/ed9780b13b42/41467_2024_50908_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/c66a6caecf73/41467_2024_50908_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/ad1248fa36c6/41467_2024_50908_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/eec9963373a2/41467_2024_50908_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/0f4a70a99880/41467_2024_50908_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/24c8fbf86534/41467_2024_50908_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/12e1951d3b53/41467_2024_50908_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/f1127569d86c/41467_2024_50908_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/c8c5013c0b9b/41467_2024_50908_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/ed9780b13b42/41467_2024_50908_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/c66a6caecf73/41467_2024_50908_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/ad1248fa36c6/41467_2024_50908_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2052/11303763/eec9963373a2/41467_2024_50908_Fig9_HTML.jpg

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