SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity.
SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity.
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DOI：
10.1038/s41467-023-41593-z
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发表时间：
2023-09-22
影响因子：
16.6
通讯作者：
Li, Ke
中科院分区：
文献类型：
--
作者：
Wang, Feng;Gao, Yang;Xue, Situ;Zhao, Luyao;Jiang, Huimin;Zhang, Tingting;Li, Yunxuan;Zhao, Chenxi;Wu, Fan;Siqin, Tana;Liu, Ying;Wu, Jie;Yan, Yechao;Yuan, Jian;Jiang, Jian-dong;Li, Ke
具有独特代谢特征的肿瘤干细胞（Cancer stem cells，CSC）被认为是导致肝细胞癌（hepatocellular carcinoma，HCC）发生、转移和治疗耐药的主要原因。在这里，我们在来自HCC细胞的肿瘤球中进行了代谢基因CRISPR/Cas9敲除文库筛选，发现SCARB 2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Scarb 2的敲除可减弱HCC的发生和进展。从机制上讲，SCARB 2与MYC的结合通过干扰HDCA 3介导的MYC在赖氨酸148上的脱乙酰化来促进MYC乙酰化，并随后增强MYC转录活性。对FDA（食品和药物管理局）批准的药物的数据库的筛选显示多粘菌素B显示出对SCARB 2蛋白的高结合亲和力，破坏SCARB 2-MYC相互作用，降低MYC活性，并降低肿瘤负荷。我们的研究将SCARB 2确定为HCC的功能驱动因素，并建议基于多粘菌素B的治疗作为HCC的靶向治疗选择。已知癌症干细胞会促进肝细胞癌（HCC）的发生、转移和耐药性。在这里，作者通过增强MYC活性将SCARB 2确定为肿瘤起始细胞的驱动因素，并在HCC的临床前模型中使用FDA批准的药物多粘菌素B评估靶向这种相互作用的有效性。
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. Cancer stem cells are known to promote hepatocellular carcinoma (HCC) initiation, metastasis and resistance. Here, the authors identify SCARB2 as a driver of tumour-initiating cells via enhanced MYC activity and evaluate the efficacy of targeting this interaction using an FDA approved drug, Polymyxin-B, in preclinical models of HCC.
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影响因子：
8.8
作者：
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通讯作者：
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