Recent evidence has highlighted the role of N 6-methyladenosine (m6A) in the regulation of mRNA expression, stability, and translation, supporting a potential role for posttranscriptional regulation mediated by m6A in cancer. Here, we explore prostate cancer as an exemplar and demonstrate that low levels of N 6-adenosine-methyltransferase ( METTL3 ) is associated with advanced metastatic disease. To investigate this relationship, we generated the first prostate m6A maps, and further examined how METTL3 regulates expression at the level of transcription, translation, and protein. Significantly, transcripts encoding extracellular matrix proteins are consistently upregulated with METTL3 knockdown. We also examined the relationship between METTL3 and androgen signaling and discovered the upregulation of a hepatocyte nuclear factor–driven gene signature that is associated with therapy resistance in prostate cancer. Significantly, METTL3 knockdown rendered the cells resistant to androgen receptor antagonists via an androgen receptor–independent mechanism driven by the upregulation of nuclear receptor NR5A2/LRH-1 . Implications: These findings implicate changes in m6A as a mechanism for therapy resistance in metastatic prostate cancer. This article is featured in Highlights of This Issue, [p. 1249][1] [1]: /lookup/volpage/19/1249?iss=8

中文翻译：

---

m6A 及其在前列腺癌中的调控靶点的定位揭示了 METTL3 低诱导治疗耐药性

最近的证据强调了 N 6-甲基腺苷 (m6A) 在 mRNA 表达、稳定性和翻译调节中的作用，支持 m6A 介导的转录后调节在癌症中的潜在作用。在这里，我们以前列腺癌为例进行探讨，并证明低水平的 N 6-腺苷甲基转移酶 (METTL3) 与晚期转移性疾病相关。为了研究这种关系，我们生成了第一张前列腺 m6A 图，并进一步检查了 METTL3 如何在转录、翻译和蛋白质水平上调节表达。值得注意的是，编码细胞外基质蛋白的转录本随着 METTL3 敲低而持续上调。我们还检查了 METTL3 和雄激素信号传导之间的关系，并发现了与前列腺癌治疗耐药性相关的肝细胞核因子驱动基因特征的上调。值得注意的是，METTL3 敲低通过核受体 NR5A2/LRH-1 上调驱动的雄激素受体非依赖性机制使细胞对雄激素受体拮抗剂产生耐药性。意义：这些发现表明 m6A 的变化是转移性前列腺癌治疗耐药的一种机制。这篇文章刊登在本期要闻中，[p。1249][1][1]:/lookup/volpage/19/1249?iss=8 METTL3 敲低通过核受体 NR5A2/LRH-1 上调驱动的雄激素受体非依赖性机制使细胞对雄激素受体拮抗剂产生耐药性。意义：这些发现表明 m6A 的变化是转移性前列腺癌治疗耐药的一种机制。这篇文章刊登在本期要闻中，[p。1249][1][1]:/lookup/volpage/19/1249?iss=8 METTL3 敲低通过核受体 NR5A2/LRH-1 上调驱动的雄激素受体非依赖性机制使细胞对雄激素受体拮抗剂产生耐药性。意义：这些发现表明 m6A 的变化是转移性前列腺癌治疗耐药的一种机制。这篇文章刊登在本期要闻中，[p。1249][1][1]:/lookup/volpage/19/1249?iss=8