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MIF4G domain containing protein regulates cell cycle and hepatic carcinogenesis by antagonizing CDK2-dependent p27 stability

Oncogene volume 34, pages 237–245 (2015)Cite this article

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Abstract

The CDK inhibitor p27kip1 plays crucial roles in cell cycle regulation and cancer progression. Through yeast two-hybrid screening, we identified MIF4G domain containing protein (MIF4GD) as a novel binding partner for p27. The association of MIF4GD and p27 was verified using immunoprecipitation and glutathione S-transferase (GST) pull-down assays. Interaction with MIF4GD led to the stabilization of p27 both in the nucleus and in the cytoplasm in hepatocellular carcinoma (HCC) cells as a result of suppressed phosphorylation of p27 by CDK2 at threonine187. Serum stimulation decreased the levels of MIF4GD and p27 simultaneously. In addition, MIF4GD overexpression resulted in increased p27 levels and reduced cell proliferation, while knockdown of MIF4GD promoted cell cycle progression with decreased p27 levels in cells. Furthermore, overexpression of MIF4GD reduced colony formation and inhibited xenograft tumor growth in nude mice. Finally, we found that both MIF4GD and p27 were expressed at low levels in HCC tissues compared to non-cancerous tissues, and that low expression levels of MIF4GD and p27 were associated with significantly worse prognosis in HCC patients. Our results suggest that MIF4GD is a potential regulator of p27-dependent cell proliferation in HCC. These findings provide a rational framework for the development of potential HCC therapy by targeting the MIF4GD–p27 interaction.

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Acknowledgements

We thank Professor Joel Belasco of New York University School of Medicine for the generous gift of pCL-6E1 and pCL-6E1.HSL constructs. This work was supported by Grants from National Basic Research Program of China (973 Program, No. 2012CB822104, and No. 2011CB910604), the National Natural Science Foundation of China (No. 31070723, No. 31270802, No. 81272708 and No. 81300720), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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  1. C Wan and S Hou: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Public Health, Nantong University, Nantong, People’s Republic of China

    C Wan & G Xu

  2. Department of Gastroenterology, Nantong University, Nantong, People’s Republic of China

    S Hou, R Ni, L Lv & X Huang

  3. Department of Immunology, Nantong University, Nantong, People’s Republic of China

    Z Ding, Q Hang, S He, Y Wang, C Cheng, X X Gu & A Shen

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  1. C Wan
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Correspondence to A Shen.

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Wan, C., Hou, S., Ni, R. et al. MIF4G domain containing protein regulates cell cycle and hepatic carcinogenesis by antagonizing CDK2-dependent p27 stability. Oncogene 34, 237–245 (2015). https://doi.org/10.1038/onc.2013.536

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