SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity.
Feng WangYang GaoSitu XueLuyao ZhaoHuimin JiangTingting ZhangYunxuan LiChenxi ZhaoFan WuTana SiqinYing LiuJie WuYechao YanJian YuanJian-Dong JiangKe LiPublished in: Nature communications (2023)
CSCs (Cancer stem cells) with distinct metabolic features are considered to cause HCC (hepatocellular carcinoma) initiation, metastasis and therapeutic resistance. Here, we perform a metabolic gene CRISPR/Cas9 knockout library screen in tumorspheres derived from HCC cells and find that deletion of SCARB2 suppresses the cancer stem cell-like properties of HCC cells. Knockout of Scarb2 in hepatocytes attenuates HCC initiation and progression in both MYC-driven and DEN (diethylnitrosamine)-induced HCC mouse models. Mechanistically, binding of SCARB2 with MYC promotes MYC acetylation by interfering with HDCA3-mediated MYC deacetylation on lysine 148 and subsequently enhances MYC transcriptional activity. Screening of a database of FDA (Food and Drug Administration)-approved drugs shows Polymyxin B displays high binding affinity for SCARB2 protein, disrupts the SCARB2-MYC interaction, decreases MYC activity, and reduces the tumor burden. Our study identifies SCARB2 as a functional driver of HCC and suggests Polymyxin B-based treatment as a targeted therapeutic option for HCC.
Keyphrases
- transcription factor
- cancer stem cells
- induced apoptosis
- cell cycle arrest
- crispr cas
- drug administration
- signaling pathway
- gene expression
- dna binding
- endoplasmic reticulum stress
- cell death
- mouse model
- genome wide
- cell proliferation
- risk assessment
- drug delivery
- dna methylation
- diabetic rats
- pi k akt
- copy number
- small molecule
- histone deacetylase
- replacement therapy