N7-甲基鸟苷（m7G）修饰是除了m6A修饰外较常见的一种表观遗传修饰，在mRNA帽子、mRNA内部、转移RNA（tRNA）、pri-miRNA和核糖体RNA（rRNA）中主要存在。已经发现m7G修饰在mRNA转录、tRNA稳定性、rRNA加工成熟和miRNA生物合成中起着重要作用。然而，m7G修饰及其在肿瘤中特别是前列腺癌（PCa）中的mRNA内的作用及其"写入"酶甲基转移酶1（METTL1）尚未揭示。通过RNA-seq和体外实验评估了雄激素敏感型前列腺癌（HSPC）和去势抵抗型前列腺癌（CRPC）之间METTL1的差异表达水平。通过体外和体内实验研究了METTL1对CRPC进展的影响。通过染色质免疫沉淀定量逆转录聚合酶链反应（CHIP-qPCR）、共免疫沉淀（Co-IP）、荧光素酶报告基因实验、转录组测序、m7G AlkAniline-Seq和mRNA降解实验等，探索了METTL1表达上调的上游分子机制和其作用的下游机制。结果与结论：在这里，我们发现METTL1在CRPC中升高，METTL1升高的患者倾向于预后不良。功能上，METTL1在CRPC细胞中的沉默明显限制了细胞增殖和侵袭能力。从机制上看，我们揭示了P300能够与SP1形成复合物，并通过SP1结合METTL1基因的启动子区域，从而介导CRPC中METTL1的转录上调。随后，我们的发现表明METTL1通过在其mRNA内添加m7G修饰，促进了CDK14的mRNA稳定性，最终促进了CRPC的进展。©2023年。意大利国家癌症研究所“Regina Elena”。

N7-methylguanosine (m7G) modification is, a more common epigenetic modification in addition to m6A modification, mainly found in mRNA capsids, mRNA interiors, transfer RNA (tRNA), pri-miRNA, and ribosomal RNA (rRNA). It has been found that m7G modifications play an important role in mRNA transcription, tRNA stability, rRNA processing maturation, and miRNA biosynthesis. However, the role of m7G modifications within mRNA and its "writer" methyltransferase 1(METTL1) in tumors, particularly prostate cancer (PCa), has not been revealed.The differential expression level of METTL1 between hormone-sensitive prostate cancer (HSPC) and castrate-resistant prostate cancer (CRPC) was evaluated via RNA-seq and in vitro experiments. The effects of METTL1 on CRPC progression were investigated through in vitro and in vivo assays. The upstream molecular mechanism of METTL1 expression upregulation and the downstream mechanism of its action were explored via Chromatin Immunoprecipitation quantitative reverse transcription polymerase chain reaction (CHIP-qPCR), Co-immunoprecipitation (Co-IP), luciferase reporter assay, transcriptome-sequencing, m7G AlkAniline-Seq, and mRNA degradation experiments, etc. RESULTS AND CONCLUSION: Here, we found that METTL1 was elevated in CRPC and that patients with METTL1 elevation tended to have a poor prognosis. Functionally, the knockdown of METTL1 in CRPC cells significantly limited cell proliferation and invasive capacity. Mechanistically, we unveiled that P300 can form a complex with SP1 and bind to the promoter region of the METTL1 gene via SP1, thereby mediating METTL1 transcriptional upregulation in CRPC. Subsequently, our findings indicated that METTL1 leads to enhanced mRNA stability of CDK14 by adding m7G modifications inside its mRNA, ultimately promoting CRPC progression.© 2023. Italian National Cancer Institute ‘Regina Elena’.