Zhang Limei, Wang Jinfu, Gui Fenfang, Peng Fanzhou, Deng Weiping, Zhu Qian
Department of Gastroenterology, Shenzhen Longhua District Central Hospital, No.187, Guanlan Street, Shenzhen, 518110, China.
Clin Transl Oncol. 2025 May;27(5):2256-2268. doi: 10.1007/s12094-024-03701-3. Epub 2024 Sep 29.
Hepatocellular carcinoma (HCC) is a lethal disease with a high mortality rate, and its development is influenced by various molecular mechanisms. Zinc finger protein 384 (ZNF384) has been reported to be involved in the progression of several cancers; however, its role in HCC remains elusive.
mRNA expression levels were analyzed by quantitative real-time polymerase chain reaction, while western blotting and immunohistochemistry were performed to validate protein expression. Cell proliferation, apoptosis, and metabolic activities were examined using clonogenicity, flow cytometry, and specific assay kits. A xenograft mouse model was employed to assess the impact of acyl-CoA synthetase medium-chain family member 1 (ACSM1) depletion on HCC cell malignancy in vivo. Chromatin immunoprecipitation assay and dual-luciferase reporter assay were conducted to explore the association between ZNF384 and ACSM1.
We found that ACSM1 and ZNF384 were significantly upregulated in HCC tissues and cells when compared with normal liver tissues and human liver immortalized cells. Knockdown of ACSM1 inhibited HCC cell proliferation and glucose metabolism and induced cell apoptosis. Furthermore, ACSM1 depletion suppressed the malignant progression of HCC cells in vivo. Our data indicated that ZNF384 transcriptionally activated ACSM1 in HCC cells. Overexpression of ACSM1 reversed the inhibitory effect of ZNF384 depletion on HCC cell malignancy. Further, methyltransferase-like 3 (METTL3) stabilized ZNF384 mRNA through m6A methylation.
METTL3-mediated m6A modification of ZNF384 contributed to the progression of HCC by transcriptionally activating ACSM1. This finding suggests potential therapeutic targets for this devastating disease.
肝细胞癌（HCC）是一种死亡率很高的致命疾病，其发展受多种分子机制影响。据报道，锌指蛋白384（ZNF384）参与多种癌症的进展；然而，其在HCC中的作用仍不清楚。
通过定量实时聚合酶链反应分析mRNA表达水平，同时进行蛋白质印迹和免疫组织化学以验证蛋白质表达。使用克隆形成试验、流式细胞术和特定检测试剂盒检测细胞增殖、凋亡和代谢活性。采用异种移植小鼠模型评估酰基辅酶A合成酶中链家族成员1（ACSM1）缺失对体内HCC细胞恶性程度的影响。进行染色质免疫沉淀试验和双荧光素酶报告基因试验以探讨ZNF384与ACSM1之间的关联。
我们发现，与正常肝组织和人肝永生化细胞相比，ACSM1和ZNF384在HCC组织和细胞中显著上调。敲低ACSM1可抑制HCC细胞增殖和葡萄糖代谢并诱导细胞凋亡。此外，ACSM1缺失抑制了体内HCC细胞的恶性进展。我们的数据表明，ZNF384在HCC细胞中转录激活ACSM1。ACSM1的过表达逆转了ZNF384缺失对HCC细胞恶性程度的抑制作用。此外，甲基转移酶样3（METTL3）通过m6A甲基化稳定ZNF384 mRNA。
METTL3介导的ZNF384的m6A修饰通过转录激活ACSM1促进了HCC的进展。这一发现为这种毁灭性疾病提示了潜在的治疗靶点。
