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Gankyrin facilitates follicle-stimulating hormone-driven ovarian cancer cell proliferation through the PI3K/AKT/HIF-1α/cyclin D1 pathway

Oncogene volume 35, pages 2506–2517 (2016)Cite this article

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Abstract

Gankyrin is a regulatory subunit of the 26kD proteasome complex. As a novel oncoprotein, gankyrin is expressed aberrantly in cancers from several different sites and has been shown to contribute to oncogenesis in endometrial and cervical carcinomas. Neither gankyrin’s contribution to the development of epithelial ovarian cancer nor its interaction with follicle-stimulating hormone (FSH)-driven proliferation in ovarian cancer has been studied. Here we have found that gankyrin is overexpressed in ovarian cancers compared with benign ovarian cystadenomas and that gankyrin regulates FSH upregulation of cyclin D1. Importantly, gankyrin regulates PI3K/AKT signaling by downregulating PTEN. Prolonged AKT activation by FSH stimulation of the FSH receptor (FSHR) promotes gankyrin expression, which, in turn, enhances AKT activation by inhibiting PTEN. Overexpression of gankyrin decreases hypoxia inducible factor-1α (HIF-1α) protein levels, but has little effect on HIF-1α mRNA levels, which could be attributed to gankyrin mediating HIF-1α protein stability via the ubiquitin–proteasome pathway. Reduction in HIF-1α protein stability led to attenuation of the binding with cyclin D1 promoter, resulted in abolishment of the negative regulation of cyclin D1 by HIF-1α, which promotes proliferation of ovarian cancer cells. Our results document that gankyrin regulates HIF-1α protein stability and cyclin D1 expression, ultimately mediating FSH-driven ovarian cancer cell proliferation.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (grant numbers 81272883, 81202044, 81370074 and 81172478), the Science and Technology Commission of Shanghai Municipality (grant number 12ZR1447600), the Shanghai Municipal Public Health Bureau (grant number XYQ2013119) and the ‘Chenxing Project’ from Shanghai Jiao Tong University to ZZ. The role of YY in this project was partially supported by The National Foundation for Cancer Research and contributions from Stuart and Gaye Lynn Zarrow.

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  1. J Chen and M Bai: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai, China

    J Chen, M Bai, B Xie, J Zhang, D Yan, X Xi, Z Zhang & Y Feng

  2. Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China

    C Ning, X Chen & Y Yu

  3. Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China

    H Liao

  4. Department of Neuropathology, Huashan Hospital of Fudan University, Shanghai, China

    J Xiong

  5. Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China

    X Tao

  6. Department of Experimental Therapeutics, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA

    Y Yu & R C Bast

  7. Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA

    W Zheng

  8. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    W Zheng

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Chen, J., Bai, M., Ning, C. et al. Gankyrin facilitates follicle-stimulating hormone-driven ovarian cancer cell proliferation through the PI3K/AKT/HIF-1α/cyclin D1 pathway. Oncogene 35, 2506–2517 (2016). https://doi.org/10.1038/onc.2015.316

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