PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Sternness Activities in Hepatocellular Carcinoma through CRAF Methylation
PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Sternness Activities in Hepatocellular Carcinoma through CRAF Methylation
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DOI：
10.1016/j.celrep.2018.09.053
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发表时间：
2018-10-16
期刊：
影响因子：
8.8
通讯作者：
Ma, Stephanie
中科院分区：
文献类型：
--
作者：
Chan, Lok Hei;Zhou, Lei;Ma, Stephanie
精氨酸甲基化是一种翻译后修饰，在决定细胞命运的信号转导和基因转录过程中起着关键作用。我们发现蛋白甲基转移酶6 （PRMT6）在肝细胞癌（HCC）中经常下调，其表达与HCC患者的侵袭性癌症特征呈负相关。PRMT6的沉默促进了HCC细胞系和患者源性类器官的肿瘤启动、转移和治疗耐药潜力。在化学诱导的HCC PRMT6基因敲除（PRMT6(-/-)）小鼠模型中，PRMT6表达的缺失同样会加剧肝肿瘤的发生。整合转录组和蛋白-蛋白相互作用研究发现，PRMT6与crf在精氨酸100上相互作用，降低其RAS结合电位，改变其下游MEK/ERK信号传导。我们的工作描述了PRMT6在维持HCC细胞中的关键抑制功能，它通过精氨酸100上CRAF的甲基化调节RAS结合和MEK/ERK信号传导。
Arginine methylation is a post-translational modification that plays pivotal roles in signal transduction and gene transcription during cell fate determination. We found protein methyltransferase 6 (PRMT6) to be frequently downregulated in hepatocellular carcinoma (HCC) and its expression to negatively correlate with aggressive cancer features in HCC patients. Silencing of PRMT6 promoted the tumor-initiating, metastasis, and therapy resistance potential of HCC cell lines and patient-derived organoids. Consistently, loss of PRMT6 expression aggravated liver tumorigenesis in a chemical-induced HCC PRMT6 knockout (PRMT6(-/-)) mouse model. Integrated transcriptome and protein-protein interaction studies revealed an enrichment of genes implicated in RAS signaling and showed that PRMT6 interacted with CRAF on arginine 100, which decreased its RAS binding potential and altered its downstream MEK/ERK signaling. Our work describes a critical repressive function for PRMT6 in maintenance of HCC cells by regulating RAS binding and MEK/ERK signaling via methylation of CRAF on arginine 100.