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

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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2019-05, Vol.79 (9), p.2379-2391
Main Authors: Takai, Atsushi, Dang, Hien, Oishi, Naoki, Khatib, Subreen, Martin, Sean P, Dominguez, Dana A, Luo, Ji, Bagni, 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
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - pathology
Carcinoma, Hepatocellular - therapy
Cell Proliferation
Epithelial Cell Adhesion Molecule - genetics
Epithelial Cell Adhesion Molecule - metabolism
Gene Expression Regulation, Neoplastic
Genome, Human
Humans
Liver Neoplasms - genetics
Liver Neoplasms - pathology
Liver Neoplasms - therapy
Metalloendopeptidases - antagonists & inhibitors
Metalloendopeptidases - genetics
Mice
Mice, Nude
Mitochondrial Processing Peptidase
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Protein Subunits
RNA Interference
Tumor Cells, Cultured
Wnt Signaling Pathway
Xenograft Model Antitumor Assays
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Summary: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/β-catenin signaling and HCC cell growth. We further characterized the top candidate PMPCB, which plays a role in mitochondrial protein processing, as a target for EpCAM HCC. PMPCB blockage suppressed EpCAM expression and Wnt/β-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. SIGNIFICANCE: This study identifies PMPCB as critical to mitochondrial homeostasis and a synthetic lethal candidate that selectively kills highly resistant EpCAM HCC tumors by inactivating the Wnt/β-catenin signaling pathway.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-18-3015