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

Abstract

Hepatocellular carcinoma (HCC) is a genetically heterogeneous disease for which a dominant actionable molecular driver has not been identified. Patients with the stem celllike EpCAM þ AFP þ 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 þ AFP þ HCC subtype. We identified 26 candidate genes linked to EpCAM/Wnt/ b-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 þ HCC. PMPCB blockage suppressed EpCAM expression and Wnt/b-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 þ HCC subpopulations. Significance: This study identifies PMPCB as critical to mitochondrial homeostasis and a synthetic lethal candidate that selectively kills highly resistant EpCAM þ HCC tumors by inactivating the Wnt/b-catenin signaling pathway.

PKM2 inhibition may reverse therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma

“…As with any proposed targeted therapy, a drug should ideally be specific, minimizing off-target effects while maintaining an acceptable burden of adverse events. While RNA interference has proven to be a successful tool in identification and validation of potential lethal targets in cancer research, its application in clinical practice is limited [31,32]. We therefore set out to demonstrate that a pharmacologic inhibitor of PKM2 could produce similar results.…”

Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular Carcinoma

“…In HCC, various populations of CSCs have been isolated from primary tumors and show distinct characteristics and contribute to tumor growth and metastasis (Tang et al, 2012;Yamashita et al, 2013;Yang et al, 2008). For instance, 30%-40% of HCCs express the epithelial cell adhesion molecule (EpCAM), and the EPCAM + cells display features of hepatic progenitor cells and activated Wnt-b-catenin signaling and are highly tumorigenic (Takai et al, 2019;Yamashita et al, 2008). HCC cells expressing the aldehyde dehydrogenase (ALDH) 1A1 activity or the surface marker CD133 also contain the enriched TIC population (Ma et al, 2007(Ma et al, , 2008.…”

PMPCB Silencing Sensitizes HCC Tumor Cells to Sorafenib Therapy

“…15 PMPCB blockade alone has been shown to produce mitochondrial dysfunction in both EpCAM+ HCC cells and EpCAM-HCC cells. 26 However, only EpCAM+ HCC cells undergo apoptosis in response to PMPCB blockade alone, 26 suggesting that EpCAM+ HCC cells are more dependent on PMPCB for survival. These findings suggest that combination sorafenib + Pmpcb KD therapies may be especially effective in HCC patients with EpCAM+ tumors.…”