SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity

  • Nat Commun. 2023 Sep 22;14(1):5917. doi: 10.1038/s41467-023-41593-z.
Feng Wang  #  1 ,  Yang Gao  #  1  2 ,  Situ Xue  #  1 ,  Luyao Zhao  1 ,  Huimin Jiang  1 ,  Tingting Zhang  1 ,  Yunxuan Li  1 ,  Chenxi Zhao  1 ,  Fan Wu  3 ,  Tana Siqin  3 ,  Ying Liu  1 ,  Jie Wu  1 ,  Yechao Yan  1 ,  Jian Yuan  4  5 ,  Jian-Dong Jiang  6 ,  Ke Li  7
Affiliations
  • 1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China.
  • 2. The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
  • 3. Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 100021, Beijing, China.
  • 4. Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China. [email protected].
  • 5. Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, 200120, China. [email protected].
  • 6. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China. [email protected].
  • 7. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 37739936 DOI: 10.1038/s41467-023-41593-z
Abstract

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.

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