蛋白质精氨酸甲基化是一种常见的翻译后修饰 (PTM)，由九种蛋白质精氨酸甲基转移酶 (PRMT) 催化。作为可甲基化组蛋白和非组蛋白底物的主要对称精氨酸甲基转移酶，PRMT5 在许多对发育和肿瘤发生至关重要的生物过程中发挥着关键作用。据报道，PRMT5 在包括前列腺癌 (PCa) 在内的多种癌症类型中过度表达，但对侵袭性 PCa 中 PRMT5 的确切生物学和机制理解仍然不明确。在这里，我们发现 PRMT5 在 PCa 中上调，与较差的患者生存率相关，促进 RNA 剪接损坏，并在功能上与一系列促肿瘤发生途径配合以增强肿瘤发生。通过基因敲低或药理学抑制来抑制 PRMT5，可减少平行分化的干细胞性，并阻止细胞周期进展，而不会引起明显的细胞凋亡。引人注目的是，PRMT5 抑制的抗肿瘤作用的严重程度与疾病的侵袭性相关，而 AR PCa 受到的影响较小。分子表征确定 MYC，但不是（或至少在较小程度上）AR，作为 PRMT5 的主要伙伴，形成正反馈回路，加剧 AR 和 AR-PCa 细胞的恶性肿瘤。受 PRMT5 与肿瘤免疫浸润负相关并转录抑制免疫基因程序这一令人惊讶的发现的启发，我们进一步表明，尽管 PRMT5 抑制剂 (PRMT5i) EPZ015666 或抗 PD-1 免疫疗法单独表现出有限的抗肿瘤效果，但 PRMT5i 与抗 PD-1 在体内抑制去势抵抗性 PCa (CRPC) 方面表现出卓越的功效。最后，为了通过合成致死性概念扩大 PRMT5i 的潜在用途，我们还进行了全球 CRISPR/Cas9 敲除筛选，以揭示许多已知致癌途径的临床级药物在与 PRMT5i 联合使用时可以重新用于靶向 CRPC。低剂量。总的来说，我们的研究结果为利用 PRMT5i 与免疫疗法或其他靶向疗法相结合来治疗侵袭性 PCa 奠定了基础。版权所有 © 2024。由 Elsevier B.V. 出版。

Protein arginine methylation is a common post-translational modification (PTM) catalyzed by nine protein arginine methyltransferases (PRMTs). As the major symmetric arginine methyltransferase that methylates both histone and non-histone substrates, PRMT5 plays key roles in a number of biological processes critical for development and tumorigenesis. PRMT5 overexpression has been reported in multiple cancer types including prostate cancer (PCa), but the exact biological and mechanistic understanding of PRMT5 in aggressive PCa remains ill-defined. Here, we show that PRMT5 is upregulated in PCa, correlates with worse patient survival, promotes corrupted RNA splicing, and functionally cooperates with an array of pro-tumorigenic pathways to enhance oncogenesis. PRMT5 inhibition via either genetic knockdown or pharmacological inhibition reduces stemness with paralleled differentiation and arrests cell cycle progression without causing appreciable apoptosis. Strikingly, the severity of antitumor effect of PRMT5 inhibition correlates with disease aggressiveness, with AR+ PCa being less affected. Molecular characterization pinpoints MYC, but not (or at least to a lesser degree) AR, as the main partner of PRMT5 to form a positive feedback loop to exacerbate malignancy in both AR+ and AR- PCa cells. Inspired by the surprising finding that PRMT5 negatively correlates with tumor immune infiltration and transcriptionally suppresses an immune-gene program, we further show that although PRMT5 inhibitor (PRMT5i) EPZ015666 or anti-PD-1 immunotherapy alone exhibits limited antitumor effects, combination of PRMT5i with anti-PD-1 displays superior efficacy in inhibiting castration-resistant PCa (CRPC) in vivo. Finally, to expand the potential use of PRMT5i through a synthetic lethality concept, we also perform a global CRISPR/Cas9 knockout screen to unravel that many clinical-grade drugs of known oncogenic pathways can be repurposed to target CRPC when used in combination with PRMT5i at low doses. Collectively, our findings establish a rationale to exploit PRMT5i in combination with immunotherapy or other targeted therapies to treat aggressive PCa.Copyright © 2024. Published by Elsevier B.V.