Department of Andrology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.
Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.
Hum Genet. 2024 Jul;143(7):857-874. doi: 10.1007/s00439-023-02603-8. Epub 2023 Sep 27.
Nonmutational epigenetic reprogramming is a crucial mechanism contributing to the pronounced heterogeneity of prostate cancer (PCa). Among these mechanisms, N6-methyladenosine (m6A)-modified long non-coding RNAs (lncRNAs) have emerged as key players. However, the precise roles of m6A-modified lncRNAs in PCa remain to be elucidated. In this study, methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted on primary and metastatic PCa samples, leading to the identification of 21 lncRNAs exhibiting differential methylation and expression patterns. We further established a PCa prognostic signature, named m6A-modified lncRNA score (mLs), based on 9 differential methylated lncRNAs in 4 multicenter cohorts. The high mLs score cohort exhibited a tendency for earlier biochemical recurrence (BCR) compared to the low mLs score cohort. Remarkably, the predictive performance of the mLs score surpassed that of five previously reported lncRNA-based signatures. Functional enrichment analysis underscored a negative correlation between the mLs score and lipid metabolism. Additionally, through MeRIP-qPCR, we pinpointed a hub gene, MIR210HG, which was validated through in vitro and in vivo experiments. These findings collectively illuminate the landscape of m6A-methylated lncRNAs in PCa tissue via MeRIP-seq and harness this information to prognosticate PCa outcomes using the mLs score. Furthermore, our study validates, both experimentally and mechanistically, the facilitative role of MIR210HG in driving PCa progression.
非突变表观遗传重编程是导致前列腺癌（PCa）显著异质性的关键机制。在这些机制中，N6-甲基腺苷（m6A）修饰的长非编码 RNA（lncRNA）已成为关键因素。然而，m6A 修饰的 lncRNA 在 PCa 中的确切作用仍有待阐明。在这项研究中，对原发性和转移性 PCa 样本进行了 m6A 修饰 RNA 免疫沉淀测序（MeRIP-seq），确定了 21 个具有差异甲基化和表达模式的 lncRNA。我们进一步基于 4 个多中心队列中 9 个差异甲基化 lncRNA 建立了一个 PCa 预后标志，命名为 m6A 修饰 lncRNA 评分（mLs）。高 mLs 评分组与低 mLs 评分组相比，生化复发（BCR）的倾向更早。值得注意的是，mLs 评分的预测性能超过了以前报道的基于 5 个 lncRNA 的特征。功能富集分析强调了 mLs 评分与脂质代谢之间的负相关。此外，通过 MeRIP-qPCR，我们确定了一个枢纽基因 MIR210HG，通过体外和体内实验进行了验证。这些发现通过 MeRIP-seq 共同阐明了 m6A 甲基化 lncRNA 在 PCa 组织中的图谱，并利用 mLs 评分预测 PCa 结局。此外，我们的研究从实验和机制上验证了 MIR210HG 在促进 PCa 进展中的促进作用。
