Arginine methyltransferases critically regulate cellular homeostasis by modulating the functional outcome of their substrates. The protein arginine methyltransferase 5 (PRMT5) is an enzyme involved in growth and survival pathways promoting tumorigenesis. However, little is known about the biologic function of PRMT5 and its therapeutic potential in multiple myeloma (MM). In the present study, we identified and validated PRMT5 as a new therapeutic target in MM. PRMT5 is overexpressed in patient MM cells and associated with decreased progression-free survival and overall survival. Either genetic knockdown or pharmacological inhibition of PRMT5 with the inhibitor EPZ015666 significantly inhibited growth of both cell lines and patient MM cells. Furthermore, PRMT5 inhibition abrogated NF-κB signaling. Interestingly, mass spectrometry identified a tripartite motif-containing protein 21 TRIM21 as a new PRMT5-partner, and we delineated a TRIM21-dependent mechanism of NF-κB inhibition. Importantly, oral administration of EPZ015666 significantly decreased MM growth in a humanized murine model of MM. These data both demonstrate the oncogenic role and prognostic relevance of PRMT5 in MM pathogenesis, and provide the rationale for novel therapies targeting PRMT5 to improve patient outcome.

中文翻译：

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蛋白质精氨酸甲基转移酶 5 具有预后相关性，是多发性骨髓瘤的药物靶标。


精氨酸甲基转移酶通过调节其底物的功能结果来严格调节细胞稳态。蛋白质精氨酸甲基转移酶 5 (PRMT5) 是一种参与促进肿瘤发生的生长和生存途径的酶。然而，人们对 PRMT5 的生物学功能及其在多发性骨髓瘤 (MM) 中的治疗潜力知之甚少。在本研究中，我们确定并验证了 PRMT5 作为 MM 的新治疗靶点。 PRMT5 在患者 MM 细胞中过度表达，并与无进展生存期和总生存期降低相关。 PRMT5 的基因敲除或抑制剂 EPZ015666 的药理抑制均显着抑制细胞系和患者 MM 细胞的生长。此外，PRMT5 抑制消除了 NF-κB 信号传导。有趣的是，质谱法鉴定出含有三联基序的蛋白质 21 TRIM21 作为新的 PRMT5 伙伴，并且我们描述了 TRIM21 依赖性的 NF-κB 抑制机制。重要的是，口服 EPZ015666 显着降低了 MM 人源化小鼠模型中 MM 的生长。这些数据既证明了 PRMT5 在 MM 发病机制中的致癌作用和预后相关性，又为针对 PRMT5 的新疗法改善患者预后提供了理论依据。