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DEK promotes HPV-positive and -negative head and neck cancer cell proliferation

Oncogene volume 34, pages 868–877 (2015)Cite this article

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Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and patient outcomes using current treatments remain poor. Tumor development is etiologically associated with tobacco or alcohol use and/or human papillomavirus (HPV) infection. HPV-positive HNSCCs, which frequently harbor wild-type p53, carry a more favorable prognosis and are a biologically distinct subgroup when compared with their HPV-negative counterparts. HPV E7 induces expression of the human DEK gene, both in vitro and in vivo. In keratinocytes, DEK overexpression is sufficient for causing oncogenic phenotypes in the absence of E7. Conversely, DEK loss results in cell death in HPV-positive cervical cancer cells at least in part through p53 activation, and Dek knockout mice are relatively resistant to the development of chemically induced skin papillomas. Despite the established oncogenic role of DEK in HPV-associated cervical cancer cell lines and keratinocytes, a functional role of DEK has not yet been explored in HNSCC. Using an established transgenic mouse model of HPV16 E7-induced HNSCC, we demonstrate that Dek is required for optimal proliferation of E7-transgenic epidermal cells and for the growth of HNSCC tumors. Importantly, these studies also demonstrate that DEK protein is universally upregulated in both HPV-positive and -negative human HNSCC tumors relative to adjacent normal tissue. Furthermore, DEK knockdown inhibited the proliferation of HPV-positive and -negative HNSCC cells, establishing a functional role for DEK in human disease. Mechanistic studies reveal that attenuated HNSCC cell growth in response to DEK loss was associated with reduced expression of the oncogenic p53 family member, ΔNp63. Exogenous ΔNp63 expression rescued the proliferative defect in the absence of DEK, thereby establishing a functional DEK-ΔNp63 oncogenic pathway that promotes HNSCC. Taken together, our data demonstrate that DEK stimulates HNSCC cellular growth and identify ΔNp63 as a novel DEK effector.

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Acknowledgements

This work was supported by the Clinical Scientist Training Program at the University of Cincinnati (TWD), Public Health Service Grant R01 CA116316 from the NIH (SIW), NIH Training Grant T32ES007250 (AKA) and R00 CA160639 from the NIH (RJK). All flow cytometric data were acquired using equipment in the Research Flow Cytometry Core in the Division of Rheumatology at Cincinnati Children’s Hospital Medical Center, supported in part by NIH AR-47363, NIH DK78392 and NIH DK90971. We would like to acknowledge the CCHMC pathology core with excellent technical support by Meredith Taylor for Ventana HPV in situ hybridization, Dr Madhavi Kadakia for providing the HA-ΔNp63 construct, Marie Matrka for providing protein lysates, and expert technical support by Dr Ronald Waclaw for use of his Leica microscope.

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Authors and Affiliations

  1. Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    A K Adams, G E Hallenbeck, T M Wise-Draper & S I Wells

  2. Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati, Cincinnati, OH, USA

    K A Casper, Y J Patil & K M Wilson

  3. McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    R J Kimple & P F Lambert

  4. Division of Pathology & Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    D P Witte

  5. Viral Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    W Xiao & M L Gillison

  6. Pathology & Laboratory Medicine and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center/University of Cincinnati, Cincinnati, OH, USA

    K A Wikenheiser-Brokamp

  7. Division of Hematology/Oncology, University Hospital, University of Cincinnati, Cincinnati, OH, USA

    T M Wise-Draper

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Correspondence to T M Wise-Draper or S I Wells.

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Adams, A., Hallenbeck, G., Casper, K. et al. DEK promotes HPV-positive and -negative head and neck cancer cell proliferation. Oncogene 34, 868–877 (2015). https://doi.org/10.1038/onc.2014.15

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