PRMT1-Mediated Translation Regulation Is a Crucial Vulnerability of Cancer.
PRMT1-Mediated Translation Regulation Is a Crucial Vulnerability of Cancer.
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DOI：
10.1158/0008-5472.can-17-0216
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发表时间：
2017-09-01
期刊：
影响因子：
11.2
通讯作者：
Orkin SH
中科院分区：
文献类型：
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作者：
Hsu JH;Hubbell-Engler B;Adelmant G;Huang J;Joyce CE;Vazquez F;Weir BA;Montgomery P;Tsherniak A;Giacomelli AO;Perry JA;Trowbridge J;Fujiwara Y;Cowley GS;Xie H;Kim W;Novina CD;Hahn WC;Marto JA;Orkin SH
通过shRNA筛选，我们发现蛋白精氨酸甲基转移酶Prmt1是小鼠p53/Rb-null骨肉瘤的易感干预点，而人类的同类骨肉瘤缺乏有效的治疗选择。在体外和体内，p53缺陷细胞中Prmt1的缺失会损害肿瘤的发生和维持。机制研究表明，Prmt1下游靶点的翻译相关通路丰富，暗示Prmt1参与翻译控制。特别是，Prmt1的缺失导致翻译起始复合物的精氨酸甲基化降低，从而破坏其组装并抑制翻译。p53/Rb-null细胞对p53诱导的翻译应激敏感，对阿achilles项目的人类癌细胞系数据的分析进一步揭示了Prmt1和翻译相关通路在相同的功能网络上收敛。我们提出针对Prmt1及其相关的翻译相关途径的靶向治疗为骨肉瘤和其他依赖翻译应激反应的癌症的治疗提供了机制基础。
Through an shRNA screen we identified the protein arginine methyltransferase Prmt1 as a vulnerable intervention point in murine p53/Rb-null osteosarcomas, the human counterpart of which lacks effective therapeutic options. Depletion of Prmt1 in p53-deficient cells impaired tumor initiation and maintenance in vitro and in vivo. Mechanistic studies reveal that translation-associated pathways were enriched for Prmt1 downstream targets, implicating Prmt1 in translation control. In particular, loss of Prmt1 led to a decrease in arginine methylation of the translation initiation complex, thereby disrupting its assembly and inhibiting translation. p53/Rb-null cells were sensitive to p53-induced translation stress, and analysis of human cancer cell line data from Project Achilles further revealed that Prmt1 and translation-associated pathways converged on the same functional networks. We propose that targeted therapy against Prmt1 and its associated translation-related pathways offer a mechanistic rationale for treatment of osteosarcomas and other cancers that exhibit dependencies on translation stress response.