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

Autor: Wang F; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China., Gao Y; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China.; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China., Xue S; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China., Zhao L; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China., Jiang H; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China., Zhang T; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China., Li Y; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China., Zhao C; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China., Wu F; Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 100021, Beijing, China., Siqin T; Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 100021, Beijing, China., Liu Y; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China., Wu J; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China., Yan Y; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China., Yuan J; Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China. yuanjian229@hotmail.com.; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, 200120, China. yuanjian229@hotmail.com., Jiang JD; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China. jiang.jdong@163.com., Li K; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China. like1986@163.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Sep 22; Vol. 14 (1), pp. 5917. Date of Electronic Publication: 2023 Sep 22.
DOI: 10.1038/s41467-023-41593-z
Abstrakt: 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.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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