The Histone Methyltransferase G9a Promotes Cholangiocarcinogenesis Through Regulation of the Hippo Pathway Kinase LATS2 and YAP Signaling Pathway
The Histone Methyltransferase G9a Promotes Cholangiocarcinogenesis Through Regulation of the Hippo Pathway Kinase LATS2 and YAP Signaling Pathway
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DOI：
10.1002/hep.31141
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发表时间：
2020-10-09
期刊：
影响因子：
13.5
通讯作者：
Wu, Tong
中科院分区：
文献类型：
--
作者：
Ma, Wenbo;Han, Chang;Wu, Tong
背景和目的胆管癌（Cholangiocarcinoma，CCA）是一种高度恶性的胆管上皮性肿瘤，预后差。在目前的研究中，我们提出的证据表明，组蛋白-赖氨酸甲基转移酶G9 a在人类CCA中上调，G9 a通过调节Hippo途径激酶大肿瘤抑制因子2（LATS 2）和yes相关蛋白（雅普）信号通路来增强CCA细胞的生长和侵袭力。方法与结果Kaplan-Meier生存分析显示G9 a高表达与CCA患者预后不良相关。在实验系统中，通过小干扰RNA/短发夹RNA去除G9 a或通过特异性药理学抑制剂（UNC 0642和UNC 0631）抑制G9 a可显著抑制人CCA细胞在体外和严重联合免疫缺陷小鼠中的生长。在尾静脉注射notch胞内结构域（NICD）和myr-Akt诱导的小鼠CCA中也观察到G9 a表达增加。向注射NICD/Akt的小鼠施用G9 a抑制剂UNC 0642降低了体内CCA的生长。这些发现表明，G9 a抑制可能是治疗CCA的有效治疗策略。从机制上讲，我们的数据表明，G9 a衍生的二甲基化H3 K9（H3 K9 me 2）沉默了Hippo途径激酶LATS 2的表达，这种作用导致随后致癌雅普的激活。因此，G9 a消耗或抑制降低了H3 K9 me 2的水平并恢复了LATS 2的表达，导致雅普抑制。结论G9 a通过调节LATS 2-雅普信号通路在胆管癌的发生发展中发挥重要作用，提示该通路可能是CCA治疗的潜在靶点。
Background and Aims Cholangiocarcinoma (CCA) is a highly malignant epithelial tumor of the biliary tree with poor prognosis. In the current study, we present evidence that the histone-lysine methyltransferase G9a is up-regulated in human CCA and that G9a enhances CCA cell growth and invasiveness through regulation of the Hippo pathway kinase large tumor suppressor 2 (LATS2) and yes-associated protein (YAP) signaling pathway. Approach and Results Kaplan-Meier survival analysis revealed that high G9a expression is associated with poor prognosis of CCA patients. In experimental systems, depletion of G9a by small interfering RNA/short hairpin RNA or inhibition of G9a by specific pharmacological inhibitors (UNC0642 and UNC0631) significantly inhibited human CCA cell growthin vitroand in severe combined immunodeficient mice. Increased G9a expression was also observed in mouse CCA induced by hydrodynamic tail vein injection of notch intracellular domain (NICD) and myr-Akt. Administration of the G9a inhibitor UNC0642 to NICD/Akt-injected mice reduced the growth of CCA,in vivo. These findings suggest that G9a inhibition may represent an effective therapeutic strategy for the treatment of CCA. Mechanistically, our data show that G9a-derived dimethylated H3K9 (H3K9me2) silenced the expression of the Hippo pathway kinase LATS2, and this effect led to subsequent activation of oncogenic YAP. Consequently, G9a depletion or inhibition reduced the level of H3K9me2 and restored the expression of LATS2 leading to YAP inhibition. Conclusions Our findings provide evidence for an important role of G9a in cholangiocarcinogenesis through regulation of LATS2-YAP signaling and suggest that this pathway may represent a potential therapeutic target for CCA treatment.