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.
Nat Commun. 2023 Sep 22;14(1):5917. doi: 10.1038/s41467-023-41593-z.
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.
具有独特代谢特征的 CSCs（癌症干细胞）被认为是导致 HCC（肝细胞癌）发生、转移和治疗耐药的原因。在这里，我们在源自 HCC 细胞的肿瘤球中进行代谢基因 CRISPR/Cas9 敲除文库筛选，发现 SCARB2 的缺失抑制了 HCC 细胞的癌症干细胞样特性。在 MYC 驱动和 DEN（二乙基亚硝胺）诱导的 HCC 小鼠模型中，肝细胞中 Scarb2 的敲除可减弱 HCC 的起始和进展。在机制上，SCARB2 与 MYC 结合通过干扰 HDCA3 介导的赖氨酸 148 上的 MYC 去乙酰化作用促进 MYC 乙酰化，从而增强 MYC 转录活性。对 FDA（美国食品和药物管理局）批准药物数据库的筛选表明，多粘菌素 B 对 SCARB2 蛋白具有高结合亲和力，破坏 SCARB2-MYC 相互作用，降低 MYC 活性，减少肿瘤负担。我们的研究确定了 SCARB2 是 HCC 的功能性驱动因素，并表明多粘菌素 B 为基础的治疗是 HCC 的一种靶向治疗选择。
