Epigenetic restriction of Hippo signaling by MORC2 underlies stemness of hepatocellular carcinoma cells
Epigenetic restriction of Hippo signaling by MORC2 underlies stemness of hepatocellular carcinoma cells
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MORC2 对 Hippo 信号传导的表观遗传限制是肝细胞癌细胞干性的基础
DOI：
10.1038/s41418-018-0095-6
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发表时间：
2018-12-01
影响因子：
12.4
通讯作者：
Wang, Bin
中科院分区：
文献类型：
--
作者：
Wang, Tao;Qin, Zhong-yi;Wang, Bin
进化上保守的Hippo信号通路是干细胞自我更新、分化和器官大小的关键调节因子。虽然Hippo信号传导的改变与不受控制的细胞生长和广泛的恶性肿瘤有因果关系，但Hippo通路中的基因突变并不常见，目前还不清楚Hippo通路的肿瘤抑制功能如何在人类癌症中被破坏。在这里，我们报告了一个新的表观遗传机制的海马失活的背景下，肝细胞癌（HCC）。我们确定了一个成员的micrororchidia（MORC）蛋白家族，MORC 2，作为一个抑制剂的Hippo通路，通过控制上游Hippo调节剂，神经纤维瘤病2（NF 2）和肾和脑蛋白（KIBRA）。MORC 2在NF 2和KIBRA的启动子处与DNA甲基转移酶3A（DNMT 3A）形成复合物，导致它们的DNA超甲基化和转录抑制。因此，NF 2和KIBRA是MORC 2调节融合诱导的Hippo信号传导激活和生理和病理条件下细胞生长接触抑制的关键靶点。MORC 2-NF 2/KIBRA轴对于维持体外和裸鼠中HCC细胞的自我更新、索拉非尼抗性和致癌性至关重要。此外，M0 RC 2表达在HCC组织中升高，与癌细胞的干细胞样性质和患者的疾病进展相关。总的来说，MORC 2通过促进DNA甲基化依赖的Hippo信号转导沉默来促进癌症的干性和肿瘤发生，并且可能是癌症治疗的潜在分子靶点。
The evolutionarily conserved Hippo signaling pathway is a key regulator of stem cell self-renewal, differentiation, and organ size. While alterations in Hippo signaling are causally linked to uncontrolled cell growth and a broad range of malignancies, genetic mutations in the Hippo pathway are uncommon and it is unclear how the tumor suppressor function of the Hippo pathway is disrupted in human cancers. Here, we report a novel epigenetic mechanism of Hippo inactivation in the context of hepatocellular carcinoma (HCC). We identify a member of the microrchidia (MORC) protein family, MORC2, as an inhibitor of the Hippo pathway by controlling upstream Hippo regulators,neurofibromatosis 2(NF2) andkidney and brain protein(KIBRA). Mechanistically, MORC2 forms a complex with DNA methyltransferase 3A (DNMT3A) at the promoters ofNF2andKIBRA, leading to their DNA hyper-methylation and transcriptional repression. As a result,NF2andKIBRAare crucial targets of MORC2 to regulate confluence-induced activation of Hippo signaling and contact inhibition of cell growth under both physiological and pathological conditions. The MORC2-NF2/KIBRA axis is critical for maintaining self-renewal, sorafenib resistance, and oncogenicity of HCC cells in vitro and in nude mice. Furthermore, MORC2 expression is elevated in HCC tissues, associated with stem-like properties of cancer cells, and disease progression in patients. Collectively, MORC2 promotes cancer stemness and tumorigenesis by facilitating DNA methylation-dependent silencing of Hippo signaling and could be a potential molecular target for cancer therapeutics.