Genome-Wide RNAi Screen Identifies PMPCB as a Therapeutic Vulnerability in EpCAM+ Hepatocellular Carcinoma
| Autor: | Katie Powell, Naoki Oishi, Ji Luo, Xiaoling Luo, Sean P. Martin, Hien Dang, Xiaolin Wu, Snorri S. Thorgeirsson, Qing-Hai Ye, Hu-Liang Jia, Dana A. Dominguez, Xin Wei Wang, Gary Mitchell, Rachel Bagni, Jin-Qiu Chen, Atsushi Takai, Subreen A. Khatib, Lun-Xiu Qin |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Regulation of gene expression Cancer Research Candidate gene Wnt signaling pathway Synthetic lethality Biology medicine.disease digestive system diseases 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology RNA interference 030220 oncology & carcinogenesis Hepatocellular carcinoma medicine Cancer research Mitochondrial protein processing Signal transduction neoplasms |
| Zdroj: | Cancer Research. 79:2379-2391 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-18-3015 |
| Popis: | 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 bona fide 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. |
| Databáze: | OpenAIRE |
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