Methylation of zinc-finger protein ZNF471 regulates MIS18A expression and inhibits proliferation and metastasis of hepatocellular carcinoma via negative regulation of the Wnt/β-catenin pathway, as well as enhances sensitivity to apatinib and donafenib
- Cell Signal. 2026 Sep:145:112608. doi: 10.1016/j.cellsig.2026.112608.
- 1. Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
- 2. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. Electronic address: [email protected].
- 3. Department of Respiratory and Critical Care Medicine, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, Shanxi 030032, China. Electronic address: [email protected].
- 4. Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China. Electronic address: [email protected].
The present study aimed to investigate the specific role and underlying molecular mechanism of aberrant methylation of zinc-finger protein ZNF471 in the development and progression of hepatocellular carcinoma (HCC). We first analyzed the expression and methylation levels of ZNF471 between HCC tissues and adjacent tissues using public databases. Subsequently, clinical tissue samples from HCC patients were collected to validate the expression and methylation status of ZNF471. The cellular functional assays were performed to determine the effects of ZNF471 on the proliferation, metastatic of HCC cells and sensitivity to apatinib and donafenib. Finally, transcriptome Sequencing and molecular biological techniques were combined to further elucidate the regulatory mechanism of ZNF471 in the progression of HCC. We found that the expression level of ZNF471 was significantly downregulated in HCC tissues and cell lines compared with corresponding adjacent normal tissues and normal hepatocyte cell lines, due to the aberrant methylation of CpG sites in its promoter region. The overexpression of ZNF471 markedly inhibited the proliferation and metastasis of HCC cells. Mechanistic investigations revealed that ZNF471 can interact with MIS18A and suppress the proliferation and metastasis of HCC through the negative regulation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT) process. Meanwhile, the ZNF471-MIS18A axis can increase the sensitivity of HCC cells to apatinib and donafenib. As a crucial tumor suppressor, ZNF471 exerts its anti-tumor effects by regulating the ZNF471-MIS18A-Wnt/β-catenin signaling pathway. Concurrently, the ZNF471-MIS18A axis holds promise as a potential target for enhancing the efficacy of apatinib and donafenib in HCC.