Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy.
Leukemia. 2018 Apr;32(4):996-1002. doi: 10.1038/leu.2017.334. Epub 2017 Nov 21.
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.
精氨酸甲基转移酶通过调节其底物的功能结果来严格调控细胞内稳态。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存活途径的酶。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 是 MM 的一个新的治疗靶点。PRMT5 在患者 MM 细胞中过度表达，与无进展生存期和总生存期缩短相关。无论是基因敲低还是用抑制剂 EPZ015666 抑制 PRMT5，都能显著抑制两种细胞系和患者 MM 细胞的生长。此外，PRMT5 抑制可阻断 NF-κB 信号。有趣的是，质谱鉴定出三联基序蛋白 21（TRIM21）是 PRMT5 的一个新的伴侣蛋白，我们描绘了一个依赖于 TRIM21 的 NF-κB 抑制机制。重要的是，EPZ015666 的口服给药能显著降低 MM 人源化小鼠模型中的 MM 生长。这些数据都证明了 PRMT5 在 MM 发病机制中的致癌作用和预后相关性，并为靶向 PRMT5 的新型治疗方法提供了理论依据，以改善患者的预后。
