Dynamic expression of ZNF382 and its tumor-suppressor role in hepatitis B virus-related hepatocellular carcinogenesis

Abstract

Hepatitis B virus (HBV) infection is the primary cause of hepatocellular carcinoma (HCC). Zinc-finger protein 382 (ZNF382), which belongs to zinc-finger protein family, has been documented to be downregulated in certain types of cancer. However, its role in HCC remains largely unknown. In this study, we demonstrated that ZNF382 expression was significantly elevated in HBV-infected liver cirrhosis tissues relative to HBV-negative normal liver tissues at protein levels, but not at mRNA levels, and was positively correlated with the levels of HBV DNA and hepatitis B virus X protein (HBx). Further studies revealed that ZNF382 was a target of miR-6867, and HBx promoted the translation of ZNF382 during HBV chronic infection through Erk-mediated miR-6867 inhibition. In addition, our data showed that ZNF382 was frequently downregulated by promoter methylation in HBV-related HCCs relative to HBV-infected liver cirrhosis tissues, and decreased expression of ZNF382 was strongly correlated with poor survival in early-stage HCC patients. Functional studies demonstrated that ZNF382 was a potent tumor suppressor in HCC cells through inhibiting cell proliferation, colony formation, migration, invasion, and tumorigenic potential in nude mice, and inducing cell apoptosis. Mechanistically, ZNF382 exerted its tumor-suppressor functions in HCC through transcriptionally repressing its downstream targets such as Fos proto-oncogene (FOS), Jun proto-oncogene (JUN), disheveled segment polarity protein 2 (DVL2), and frizzled class receptor 1 (FZD1), thereby impairing the activities of activating protein 1 (AP-1) and Wnt/β-catenin pathways and activating p53 signaling. Altogether, our data show that ZNF382 acts as a tumor suppressor, and is co-regulated by HBx and epigenetic mechanism in HBV-related hepatocellular carcinogenesis.

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Acknowledgements

This study was supported by the National Nature Science Foundation of China (no. 81402340, 81572627, and 81672645).

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PH and QY conceived and designed the experiments. SD, YC, and PC conducted the experiments. SD, MJ, and PH analyzed the data. JZ, BS, and PH contributed reagents and materials. SD and PH wrote the paper.

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Correspondence to Qi Yang or Peng Hou.

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Dang, S., Zhou, J., Chen, Y. et al. Dynamic expression of ZNF382 and its tumor-suppressor role in hepatitis B virus-related hepatocellular carcinogenesis. Oncogene 38, 4804–4819 (2019). https://doi.org/10.1038/s41388-019-0759-9

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