N6-methyladenosine (m6A) methylation, a prevalent epitranscriptomic modification, plays a crucial role in regulating mRNA expression, stability, and translation in mammals. M6A regulators have gained attention for their potential implications in tumorigenesis and clinical applications, such as cancer diagnosis and therapeutics. The existing literature predominantly addresses m6A regulators in the context of primary prostate cancer (PCa). However, a notable gap in the knowledge emerges regarding the dynamic expression patterns of these regulators as PCa progresses towards the castration-resistant stage (CRPC). Employing sequential window acquisition of all theoretical mass spectra (SWATH-MS) and RNAseq analysis, we comprehensively profiled the expression of 27 m6A regulators in hormone/androgen-dependent and -independent PCa cell lines, revealing distinct clustering between tumor and adjacent normal prostate tissues. High-grade PCa tumors demonstrated the upregulation ofMETTL3,RBM15B, andHNRNAPA2B1and the downregulation ofZC3H13,NUDT21, andFTO. Notably, we identified six m6A regulators associated with PCa survival. Additionally, association analysis of the PCa-associated risk loci in the cancer genome atlas program (TCGA) data unveiled genetic variations near theWTAP,HNRNPA2B1, andFTOgenes as significant expression quantitative trait loci. In summary, our study unraveled abnormalities in m6A regulator expression in PCa progression, elucidating their association with PCa risk loci. Considering the heterogeneity within the PCa phenotypes and treatment responses, our findings suggest that prognostic stratification based on m6A regulator expression could enhance PCa diagnosis and prognosis.
N6-甲基腺苷（m6A）甲基化作为一种普遍存在的表观转录组修饰，在哺乳动物中调控mRNA表达、稳定性及翻译过程中发挥关键作用。m6A调节因子因其在肿瘤发生及临床应用（如癌症诊断与治疗）中的潜在意义而备受关注。现有文献主要聚焦于原发性前列腺癌（PCa）中的m6A调节因子，然而关于这些调节因子在前列腺癌进展至去势抵抗阶段（CRPC）过程中的动态表达模式，目前仍存在显著的知识空白。通过采用连续窗口采集所有理论质谱（SWATH-MS）技术和RNAseq分析，我们系统描绘了27种m6A调节因子在激素/雄激素依赖性与非依赖性前列腺癌细胞系中的表达谱，揭示了肿瘤组织与癌旁正常前列腺组织间的显著聚类差异。高级别前列腺癌肿瘤中观察到METTL3、RBM15B和HNRNPA2B1表达上调，而ZC3H13、NUDT21和FTO表达下调。值得注意的是，我们鉴定出六种与前列腺癌生存期相关的m6A调节因子。此外，通过对癌症基因组图谱计划（TCGA）数据中前列腺癌相关风险位点的关联分析，发现WTAP、HNRNPA2B1和FTO基因附近的遗传变异是显著表达数量性状位点。综上所述，本研究揭示了前列腺癌进展过程中m6A调节因子表达的异常现象，阐明了其与前列腺癌风险位点的关联性。鉴于前列腺癌表型及治疗反应存在的异质性，我们的研究结果表明基于m6A调节因子表达的预后分层可能有助于提升前列腺癌的诊断与预后评估水平。
肿瘤(癌症)患者之家