遗传和表观遗传改变发生在许多生理和病理过程中。关于 PIWI 相互作用 RNA (piRNA) 及其遗传变异与前列腺癌 (PCa) 风险和进展之间关系的现有知识有限。在这项研究中，结合了三个全基因组关联研究数据集，包括 85,707 个 PCa 病例和 166,247 个对照，以揭示 piRNA 中的遗传变异。功能研究涉及在细胞和小鼠模型中操纵 piRNA 表达，以研究其在 PCa 中的致癌作用。确定了一种特定的基因变异 rs17201241，它与肿瘤中 PROPER（前列腺癌中过度表达的 piRNA）表达增加相关，并且位于该基因内，导致 PCa 风险增加和恶性进展。从机制上讲，PROPER 与 YTHDF2 偶联可识别 N6-甲基腺苷 (m6A)，并促进 5'-非翻译区 (UTR) 处的 EIF2S3 与 3'-UTR 处的 YTHDF2/YBX3 之间的 RNA 结合蛋白相互作用，从而促进 DUSP1 环化。这种 m6A 依赖性 mRNA 循环模式增强了 DUSP1 降解并抑制 DUSP1 翻译，最终降低 DUSP1 表达并通过 p38 丝裂原激活蛋白激酶 (MAPK) 信号通路促进 PCa 转移。使用 antagoPROPER 抑制 PROPER 表达可有效抑制异种移植物的生长，表明其作为治疗靶点的潜力。因此，针对 piRNA PROPER 介导的遗传和表观遗传精细控制是同步预防和治疗 PCa 的一种有前途的策略。© 2024 作者。 《Advanced Science》由 Wiley‐VCH GmbH 出版。

Genetic and epigenetic alterations occur in many physiological and pathological processes. The existing knowledge regarding the association of PIWI-interacting RNAs (piRNAs) and their genetic variants on risk and progression of prostate cancer (PCa) is limited. In this study, three genome-wide association study datasets are combined, including 85,707 PCa cases and 166,247 controls, to uncover genetic variants in piRNAs. Functional investigations involved manipulating piRNA expression in cellular and mouse models to study its oncogenetic role in PCa. A specific genetic variant, rs17201241 is identified, associated with increased expression of PROPER (piRNA overexpressed in prostate cancer) in tumors and are located within the gene, conferring an increased risk and malignant progression of PCa. Mechanistically, PROPER coupled with YTHDF2 to recognize N6-methyladenosine (m6A) and facilitated RNA-binding protein interactions between EIF2S3 at 5'-untranslated region (UTR) and YTHDF2/YBX3 at 3'-UTR to promote DUSP1 circularization. This m6A-dependent mRNA-looping pattern enhanced DUSP1 degradation and inhibited DUSP1 translation, ultimately reducing DUSP1 expression and promoting PCa metastasis via the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Inhibition of PROPER expression using antagoPROPER effectively suppressed xenograft growth, suggesting its potential as a therapeutic target. Thus, targeting piRNA PROPER-mediated genetic and epigenetic fine control is a promising strategy for the concurrent prevention and treatment of PCa.© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.