Identification of PRMT5 as a therapeutic target in cholangiocarcinoma [RNA-seq I]

Cholangiocarcinoma is a very aggressive cancer whose incidence is increasing. Moreover, chemotherapies are little effective and the response to immune checkpoint inhibitors is low. We have identified protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in cholangiocarcinoma. PRMT5-targeting drugs markedly inhibited CCA cells proliferation, synergizing with cisplatin and gemcitabine, and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodeling and DNA repair, consistently inducing the formation of RNA-loops and promoting DNA damage. Our findings support the evaluation of PRMT5 inhibitors in clinical trials. Overall design: To study the effect of PRMT5 inhibition in cholangiocarcinoma (CCA), the human CCA cell line HuCCT-1 was treated with PRMT5 inhibitor JNJ-64619178 or vehicle (DMSO) and we then performed gene expression profiling analysis using data obtained from RNA-seq of 3 replicates of each condition.

胆管癌（Cholangiocarcinoma, CCA）是一种侵袭性极强的恶性肿瘤，其发病率呈逐年上升趋势。此外，化疗方案的疗效甚微，免疫检查点抑制剂的客观响应率也较低。我们已鉴定出蛋白质精氨酸甲基转移酶5（Protein Arginine-Methyltransferase 5, PRMT5）作为胆管癌的新型治疗靶点。靶向PRMT5的药物可显著抑制胆管癌细胞增殖，与顺铂（cisplatin）、吉西他滨（gemcitabine）具有协同作用，并能有效阻碍胆管癌类器官的生长。抑制PRMT5会下调参与染色质重塑与DNA修复的致癌基因表达，持续诱导RNA环（RNA-loops）的形成并促进DNA损伤。本研究结果支持开展PRMT5抑制剂的临床试验评估。整体实验设计：为探究PRMT5抑制对胆管癌的作用效果，我们将人胆管癌细胞系HuCCT-1用PRMT5抑制剂JNJ-64619178或溶剂对照二甲基亚砜（DMSO）处理，随后通过每个处理组3次生物学重复的RNA测序（RNA-seq）数据开展基因表达谱分析。