SCARB2 Drives Hepatic Carcinoma Initiation by Supporting Cancer Stem Cell Traits and Enhancing MYC Transcriptional Activity

Abstract Cancer stem cells (CSCs) with distinct metabolic features are considered to cause hepatocellular carcinoma (HCC) initiation, metastasis and therapeutic resistance. Here, we performed a metabolic gene CRISPR/Cas9 knockout screen in tumorspheres derived from HCC cells and found that deletion of the scavenger receptor SCARB2 suppressed the CSC traits of HCC cells. Using lineage tracing of the Scarb2 locus in mice, we demonstrated that Scarb2 positive HCC cells showed tumor-initiating activity. Specifically, Cre-mediated recombination with oncogenic MYC expression in Scarb2 positive cells drove HCC tumor formation, as determined by lineage tracing in Scarb2 mice. Knockout of Scarb2 in hepatocytes attenuated HCC initiation and progression by inhibiting CSC self-renewal. Mechanistically, binding of SCARB2 with MYC promoted MYC acetylation by interfering with HDCA3-mediated MYC deacetylation and subsequently enhanced MYC activity. Screening of a database of FDA-approved drugs showed Polymyxin B displayed high binding affinity for SCARB2 protein, disrupted the SCARB2-MYC interaction, decreased MYC activity, and reduced the tumor burden. Our study identifies SCARB2 as a marker and functional driver of HCC CSCs and suggests a targeted therapeutic option for HCC.