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EAG1 enhances hepatocellular carcinoma proliferation by modulating SKP2 and metastasis through pseudopod formation

Oncogene volume 40, pages 163–176 (2021)Cite this article

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Abstract

Ether-à-go-go-1 (EAG1), one of the potassium channels, is involved in various physiological processes and plays an important role in the tumorigenesis of many kinds of cancer. EAG1 is highly expressed in hepatocarcinoma cells and is closely related to clinical prognosis, but the molecular mechanism remains elusive. In this study, we verified that EAG1 promotes the proliferation of hepatocellular carcinoma (HCC) both in vitro and in vivo. It promotes cell cycle progression by inhibiting the ubiquitination of SKP2. In addition, EAG1 promotes the migration and invasion of HCC by promoting cell pseudopod formation. Furthermore, in a high-pressure plasmid-injected mouse liver orthotopic carcinoma model, astemizole, an EAG family blocker, can significantly inhibit the formation of liver cancer. Meanwhile, liver-specific EAG1 knockout mice show resistance to hepatocarcinogenesis. This research demonstrated that EAG1 plays an important role in the progression of HCC, and could be a potential therapeutic target for HCC.

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Fig. 1: EAG1 promoted cell proliferation of two HCC cell lines.
Fig. 2: Changes in EAG1 affected cell cycle progression and cell cycle-related proteins.
Fig. 3: EAG1 affected SKP2 protein degradation.
Fig. 4: EAG1 promoted cell proliferation by regulating SKP2.
Fig. 5: EAG1 promoted cell migration and invasion of HCC in vitro and in vivo.
Fig. 6: Inhibition of EAG1 prevented the HCC formation.
Fig. 7: Expression of EAG1 was upregulated in HCC tissues and positively correlated with SKP2.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81272675 and 81870434) to PS, the Key Research and Development Plan of Zhejiang Province (2020C04003) to PS, the National S&T Major Project (2017ZX10203205) to SZ.

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  1. These authors contributed equally: Jun Chen, Zefeng Xuan

Authors and Affiliations

  1. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Jun Chen, Zefeng Xuan, Wenfeng Song, Hao Chen, Haiyang Xie, Shusen Zheng & Penghong Song

  2. NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China

    Jun Chen, Zefeng Xuan, Wenfeng Song, Hao Chen, Haiyang Xie, Yongchao Zhao, Shusen Zheng & Penghong Song

  3. Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China

    Jun Chen, Zefeng Xuan, Wenfeng Song, Hao Chen, Haiyang Xie, Shusen Zheng & Penghong Song

  4. Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, 310003, Zhejiang Province, China

    Jun Chen, Zefeng Xuan, Wenfeng Song, Hao Chen, Haiyang Xie, Shusen Zheng & Penghong Song

  5. Department of Lung Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Jun Chen, Weili Han & Hao Chen

  6. Division of Breast Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Zefeng Xuan

  7. Thyroid Disease Diagnosis and Treatment Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yehui Du

  8. Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China

    Yongchao Zhao

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Correspondence to Shusen Zheng or Penghong Song.

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Chen, J., Xuan, Z., Song, W. et al. EAG1 enhances hepatocellular carcinoma proliferation by modulating SKP2 and metastasis through pseudopod formation. Oncogene 40, 163–176 (2021). https://doi.org/10.1038/s41388-020-01522-6

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