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Genome-Wide RNAi Screen Identifies PMPCB as a Therapeutic Vulnerability in EpCAM(+) Hepatocellular Carcinoma

  1. Author:
    Takai, Atsushi
    Dang, Hien
    Oishi, Naoki
    Khatib, Subreen
    Martin, Sean P.
    Dominguez, Dana A.
    Luo, Ji
    Beyer,Rachel
    Wu,Xiaolin
    Powell,Katie
    Ye, Qing-Hai
    Jia, Hu-Liang
    Qin, Lun-Xiu
    Chen, Jinqiu
    Mitchell, Gary A.
    Luo, Xiaoling
    Thorgeirsson, Snorri S.
    Wang, Xin Wei

  2. Author Address

    NCI, Lab Human Carcinogenesis, Ctr Canc Res, Bethesda, MD 20892 USA.Thomas Jefferson Univ, Dept Surg, Div Surg Res, Philadelphia, PA 19107 USA.NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA.Canc Res Technol Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA.Fudan Univ, Shanghai, Peoples R China.NCI, Collaborat Prot Technol Resource, Ctr Canc Res, Bethesda, MD 20892 USA.Kyoto Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Kyoto, Japan.Kanazawa Univ, Grad Sch Med, Dept Gastroenterol, Kanazawa, Ishikawa, Japan.
    1. Year: 2019
    2. Date: May 1
  2. Journal: CANCER RESEARCH
  3. AMER ASSOC CANCER RESEARCH,
    1. 79
    2. 9
    3. Pages: 2379-2391
  5. Type of Article: Article
  6. ISSN: 0008-5472
  1. Abstract:

    Hepatocellular carcinoma (HCC) is a genetically heterogeneous disease for which a dominant actionable molecular driver has not been identified. Patients with the stem cell-like EpCAM(+) AFP(+) HCC subtype have poor prognosis. Here, we performed a genome-wide RNAi screen to identify genes with a synthetic lethal interaction with EpCAM as a potential therapeutic target for the EpCAM(+) AFP(+) HCC subtype. We identified 26 candidate genes linked to EpCAM/Wnt/beta-catenin signaling and HCC cell growth. We further characterized the top candidate PMPCB, which plays a role in mitochondrial protein processing, as a bona fide target for EpCAM(+) HCC. PMPCB blockage suppressed EpCAM expression and Wnt/beta-catenin signaling via mitochondria-related reactive oxygen species production and FOXO activities, resulting in apoptosis and tumor suppression. These results indicate that a synthetic lethality screen is a viable strategy to identify actionable drivers of HCC and identify PMPCB as a therapeutically vulnerable gene in EpCAM(+) HCC subpopulations.

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External Sources

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  2. DOI: 10.1158/0008-5472.CAN-18-3015
  3. PMID: 30862714
  4. PMCID: PMC6497533
  5. View record in Web of Science®
  6. WOS: 000466765900027

Library Notes

  1. Fiscal Year: FY2018-2019
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