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

Author

Listed:
  • Feng Wang

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Yang Gao

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital)

  • Situ Xue

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Luyao Zhao

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Huimin Jiang

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Tingting Zhang

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Yunxuan Li

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Chenxi Zhao

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Fan Wu

    (Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Tana Siqin

    (Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Ying Liu

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Jie Wu

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Yechao Yan

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Jian Yuan

    (East Hospital, Tongji University School of Medicine
    Tongji University School of Medicine)

  • Jian-dong Jiang

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Ke Li

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

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.

Suggested Citation

  • Feng Wang & Yang Gao & Situ Xue & Luyao Zhao & Huimin Jiang & Tingting Zhang & Yunxuan Li & Chenxi Zhao & Fan Wu & Tana Siqin & Ying Liu & Jie Wu & Yechao Yan & Jian Yuan & Jian-dong Jiang & Ke Li, 2023. "SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41593-z
    DOI: 10.1038/s41467-023-41593-z
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    References listed on IDEAS

    as
    1. Ke Li & Feng Wang & Zhao-na Yang & Ting-ting Zhang & Yu-fen Yuan & Chen-xi Zhao & Zaiwuli Yeerjiang & Bing Cui & Fang Hua & Xiao-xi Lv & Xiao-wei Zhang & Jiao-jiao Yu & Shan-shan Liu & Jin-mei Yu & Sh, 2020. "TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    2. Saskia Heybrock & Kristiina Kanerva & Ying Meng & Chris Ing & Anna Liang & Zi-Jian Xiong & Xialian Weng & Young Ah Kim & Richard Collins & William Trimble & Régis Pomès & Gilbert G. Privé & Wim Annaer, 2019. "Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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