Mesothelioma is a highly aggressive cancer of the mesothelial lining that is caused by exposure to asbestos. Surgical resection followed by chemotherapy is the current treatment strategy, but this is marginally successful and leads to drug-resistant disease. We are interested in factors that maintain the aggressive mesothelioma cancer phenotype as therapy targets. Protein arginine methyltransferase 5 (PRMT5) functions in concert with the methylosome protein 50 (MEP50) cofactor to catalyze symmetric dimethylation of key arginine resides in histones 3 and 4 which modifies the chromatin environment to alter tumor suppressor and oncogene expression and enhance cancer cell survival. Our studies show that PRMT5 or MEP50 loss reduces H4R3me2s formation and that this is associated with reduced cancer cell spheroid formation, invasion, and migration. Treatment with sulforaphane (SFN), a diet-derived anticancer agent, reduces PRMT5/MEP50 level and H4R3me2s formation and suppresses the cancer phenotype. We further show that SFN treatment reduces PRMT5 and MEP50 levels and that this reduction is required for SFN suppression of the cancer phenotype. SFN treatment also reduces tumor formation which is associated with reduced PRMT5/MEP50 expression and activity. These findings suggest that SFN may be a useful mesothelioma treatment agent that operates, at least in part, via suppression of PRMT5/MEP50 function.

中文翻译：

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萝卜硫素通过抑制 PRMT5 和 MEP50 功能来抑制间皮瘤癌细胞表型


间皮瘤是一种高度侵袭性的间皮癌，由接触石棉引起。手术切除后进行化疗是目前的治疗策略，但这收效甚微，并且会导致耐药性疾病。我们对维持侵袭性间皮瘤癌症表型作为治疗目标的因素感兴趣。蛋白精氨酸甲基转移酶 5 (PRMT5) 与甲基小体蛋白 50 (MEP50) 辅助因子协同作用，催化组蛋白 3 和 4 中关键精氨酸的对称二甲基化，从而改变染色质环境，从而改变抑癌基因和癌基因的表达并增强癌细胞的存活率。我们的研究表明，PRMT5 或 MEP50 缺失会减少 H4R3me2s 的形成，这与癌细胞球体形成、侵袭和迁移的减少有关。使用萝卜硫素 (SFN)（一种源自饮食的抗癌剂）治疗可降低 PRMT5/MEP50 水平和 H4R3me2s 形成并抑制癌症表型。我们进一步表明，SFN 治疗可降低 PRMT5 和 MEP50 水平，并且这种降低是 SFN 抑制癌症表型所必需的。 SFN 治疗还可以减少肿瘤形成，这与 PRMT5/MEP50 表达和活性降低有关。这些发现表明 SFN 可能是一种有用的间皮瘤治疗药物，其作用至少部分是通过抑制 PRMT5/MEP50 功能来发挥作用。