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Epigenetic restriction of Hippo signaling by MORC2 underlies stemness of hepatocellular carcinoma cells

Cell Death & Differentiationvolume 25pages20862100 (2018) | Download Citation


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) and kidney and brain protein (KIBRA). Mechanistically, MORC2 forms a complex with DNA methyltransferase 3A (DNMT3A) at the promoters of NF2 and KIBRA, leading to their DNA hyper-methylation and transcriptional repression. As a result, NF2 and KIBRA are 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.

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Edited by R. De Maria


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We thank Ms. Qing-hua Ma for her assistance in FACS analysis and sorting (Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University). We also thank Prof. Jiang Zheng and Ms. Fang-fang Li for their technical assistance in immunofluorescence staining and confocal microscopy. This work was supported by the grants from the National Natural Science Foundation of China (NSFC Nos. 81472294 to BW and 81672463 to D-fC).

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Author notes

  1. These authors contributed equally: Tao Wang, Zhong-yi Qin, Liang-zhi Wen.


  1. Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University (Army Medical University), 400042, Chongqing, China

    • Tao Wang
    • , Zhong-yi Qin
    • , Liang-zhi Wen
    • , Yan Guo
    • , Qin Liu
    • , Kai-jun Liu
    • , Xing-wei Wang
    • , Shu-jie Lai
    • , Wen-jing Sun
    • , Yan-ling Wei
    • , Lei Liu
    • , Ling Guo
    • , Yu-qin Chen
    • , Jun Wang
    • , Dong-feng Chen
    •  & Bin Wang
  2. Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, Jiangsu Province, China

    • Zeng-jie Lei
  3. Department of Medical Genetics, Second Military Medical University (Navy Medical University), 200433, Shanghai, China

    • Wei Pan
  4. Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University (Army Medical University), 400042, Chongqing, China

    • Hua-liang Xiao
  5. Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, China

    • Xiu-wu Bian


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The authors declare that they have no conflict of interest.

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Correspondence to Dong-feng Chen or Bin Wang.

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