Background: Since primary prostate cancer (PCa) can advance to the life-threatening metastatic PCa, exploring the molecular mechanisms underlying PCa metastasis is crucial for developing the novel targeted preventive strategies for decreasing the mortality of PCa. RNA N⁶-methyladenosine (m⁶A) is an emerging regulatory mechanism for gene expression and its specific roles in PCa progression remains elusive./nMethods: Western blotting, quantitative real-time PCR and immunohistochemical analyses were used to detect target gene expression in PCa cells in vitro and prostate tissues from patients. RNA immunoprecipitation was conducted to analyze the specific binding of mRNA to the target protein. Migration and invasion assays were used to assess the migratory capacities of cancer cells. The correlation between target gene expression and survival rate of PCa patients was analyzed based the TCGA database./nResults: We found that total RNA N⁶-methyladenosine (m⁶A) modification levels were markedly upregulated in human PCa tissues due to increased expression of methyltransferase like 3 (METTL3). Further studies revealed that the migratory and invasive capacities of PCa cells were markedly suppressed upon METTL3 knockdown. Mechanistically, METTL3 mediates m⁶A modification of USP4 mRNA at A2696, and m⁶A reader protein YTHDF2 binds to and induces degradation of USP4 mRNA by recruiting RNA-binding protein HNRNPD to the mRNA. Decrease of USP4 fails to remove the ubiquitin group from ELAVL1 protein, resulting in a reduction of ELAVL1 protein. Lastly, downregulation of ELAVL1 in turn increases ARHGDIA expression, promoting migration and invasion of PCa cells./nConclusions: Our findings highlight the role of METTL3 in modulating invasion and metastasis of PCa cells, providing insight into promising therapeutic strategies for hindering PCa progressing to deadly metastases.

中文翻译：

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METTL3的沉默有效阻碍前列腺癌细胞的侵袭和转移

背景：由于原发性前列腺癌 (PCa) 可以发展为危及生命的转移性 PCa，因此探索 PCa 转移的分子机制对于开发降低 PCa 死亡率的新型靶向预防策略至关重要。RNA N ⁶ -甲基腺苷 (m ⁶ A) 是一种新兴的基因表达调控机制，其在 PCa 进展中的具体作用仍然难以捉摸。/n方法：使用蛋白质印迹、实时定量 PCR 和免疫组织化学分析检测靶基因表达在体外PCa 细胞中和来自患者的前列腺组织。进行RNA免疫沉淀以分析mRNA与靶蛋白的特异性结合。迁移和侵袭测定用于评估癌细胞的迁移能力。基于TCGA database./n分析靶基因表达和PCA患者存活率之间的相关性结果：我们发现，总RNAÑ ⁶ -methyladenosine（M ⁶ A）修改水平显着上调在人类前列腺组织中由于增加的表达甲基转移酶 3 (METTL3)。进一步的研究表明，敲除 METTL3 后 PCa 细胞的迁移和侵袭能力受到显着抑制。从机制上讲，METTL3 介导 m ⁶USP4 mRNA 在 A2696 和 m ⁶ A 阅读器蛋白 YTHDF2 处的修饰通过将 RNA 结合蛋白 HNRNPD 募集到 mRNA结合并诱导USP4 mRNA降解。USP4 的减少未能从 ELAVL1 蛋白中去除泛素基团，导致 ELAVL1 蛋白的减少。最后，又将ELAVL1的下调增加ARHGDIA表达，促进前列腺癌cells./n的迁移和侵袭结论：我们的研究结果强调METTL3在调节侵袭和前列腺癌细胞的转移中的作用，提供洞察前途的治疗策略，阻碍了前列腺癌发展到致命的转移。