Prostate cancer (PCa) is the most frequently diagnosed malignancy in men, and its mechanism remains poorly understood. Therefore, it is urgent to discover potential novel diagnostic biomarkers and therapeutic targets that can potentially facilitate the development of efficient anticancer strategies. A series of functional in vitro and in vivo experiments were conducted to evaluate the biological behaviors of PCa cells. RNA pulldown, Western blot, luciferase reporter, immunohistochemistry and chromatin immunoprecipitation assays were applied to dissect the detailed underlying mechanisms. High-throughput sequencing was performed to screen for differentially expressed circRNAs in PCa and adjacent normal tissues. Upregulation of protein arginine methyltransferase 5 (PRMT5) is associated with poor progression-free survival and the activation of multiple signaling pathways in PCa. PRMT5 inhibits the transcription of CAMK2N1 by depositing the repressive histone marks H4R3me2s and H3R8me2s on the proximal promoter region of CAMK2N1, and results in malignant progression of PCa both in vitro and in vivo. Moreover, the expression of circSPON2, a candidate circRNA in PCa tissues identified by RNA-seq, was found to be associated with poor clinical outcomes in PCa patients. Further results showed that circSPON2 induced PCa cell proliferation and migration, and that the circSPON2-induced effects were counteracted by miR-331-3p. Particularly, circSPON2 acted as a competitive endogenous RNA (ceRNA) of miR-331-3p to attenuate the repressive effects of miR-331-3p on its downstream target PRMT5. Our findings showed that the epigenetic regulator PRMT5 aggravates PCa progression by inhibiting the transcription of CAMK2N1 and is modulated by the circSPON2/miR-331-3p axis, which may serve as a potential therapeutic target for patients with aggressive PCa.

中文翻译：

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circSPON2/miR-331-3p 轴调节 PRMT5，一种 CAMK2N1 转录和前列腺癌进展的表观遗传调节因子

前列腺癌 (PCa) 是男性最常被诊断出的恶性肿瘤，其机制仍知之甚少。因此，迫切需要发现潜在的新型诊断生物标志物和治疗靶点，以促进有效抗癌策略的发展。进行了一系列功能性体外和体内实验，以评估 PCa 细胞的生物学行为。应用 RNA 下拉、蛋白质印迹、荧光素酶报告基因、免疫组织化学和染色质免疫沉淀测定来剖析详细的潜在机制。进行高通量测序以筛选 PCa 和邻近正常组织中差异表达的 circRNA。蛋白质精氨酸甲基转移酶 5 (PRMT5) 的上调与较差的无进展生存期和 PCa 中多个信号通路的激活有关。PRMT5 通过在 CAMK2N1 的近端启动子区域沉积抑制性组蛋白标记 H4R3me2s 和 H3R8me2s 来抑制 CAMK2N1 的转录，并导致体外和体内 PCa 的恶性进展。此外，发现通过 RNA-seq 鉴定的 PCa 组织中的候选 circRNA circSPON2 的表达与 PCa 患者的不良临床结果相关。进一步的结果表明，circSPON2 诱导 PCa 细胞增殖和迁移，并且 circSPON2 诱导的效应被 miR-331-3p 抵消。特别，circSPON2 充当 miR-331-3p 的竞争性内源性 RNA (ceRNA)，以减弱 miR-331-3p 对其下游靶标 PRMT5 的抑制作用。我们的研究结果表明，表观遗传调节因子 PRMT5 通过抑制 CAMK2N1 的转录来加重 PCa 进展，并受 circSPON2/miR-331-3p 轴的调节，这可能作为侵袭性 PCa 患者的潜在治疗靶点。