title: DEK promotes HPV-positive and -negative head and neck cancer cell proliferation.
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.
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Adams
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: G E
authors.initials: GE
authors.lastname: Hallenbeck
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Casper
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Patil
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Wilson
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Kimple
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Lambert
authors.affiliation: Division of Pathology & Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Witte
authors.affiliation: Viral Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: W
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Viral Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Gillison
authors.affiliation: Pathology & Laboratory Medicine and Pulmonary Biology, Cincinnati Children's Hospital Medical Center/University of Cincinnati, Cincinnati, OH, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Wikenheiser-Brokamp
authors.affiliation: 1] Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA [2] Division of Hematology/Oncology, University Hospital, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Wise-Draper
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Wells
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006258:Head and Neck Neoplasms; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C519564:DEK protein, mouse; D004268:DNA-Binding Proteins; C084738:DEK protein, human; D015513:Oncogene Proteins; D050725:Papillomavirus E7 Proteins; D010750:Phosphoproteins; D000075223:Poly-ADP-Ribose Binding Proteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16