Human papillomavirus 16 E6 induces FoxM1B in oral keratinocytes through GRHL2

dc.contributor.authorChen, W.
dc.contributor.authorShimane, S.
dc.contributor.authorKawano, A.
dc.contributor.authorAlshaikh, Abdullah
dc.contributor.authorKim, S.Y.
dc.contributor.authorChung, Sang-Hyuk
dc.contributor.authorKim, R.H.
dc.contributor.authorShin, K.H.
dc.contributor.authorWalentin, Katharina
dc.contributor.authorPark, Nyun-Ho
dc.contributor.authorScmidt-Ott, Kai
dc.contributor.authorKang, Myung-Koo
dc.description.abstractHigh-risk human papillomavirus (HPV) is a major risk factor for oral and pharyngeal cancers (OPCs), yet the detailed mechanisms by which HPV promotes OPCs are not understood. Forkhead box M1B (FoxM1B) is an oncogene essential for cell cycle progression and tumorigenesis, and it is aberrantly overexpressed in many tumors. We previously showed that FoxM1B was the putative target of an epithelial-specific transcription factor, Grainyhead-like 2 (GRHL2). In the current study, we demonstrate that HPV type 16 (HPV-16) E6 induces FoxM1B in human oral keratinocytes (HOKs) and tonsillar epithelial cells (TECs) in part through GRHL2. FoxM1B was barely detectable in cultured normal human oral keratinocytes (NHOKs) and progressively increased in immortalized HOKs harboring HPV-16 genome (HOK-16B) and tumorigenic HOK-16B/BaP-T cells. Retroviral expression of HPV-16 E6 and/or E7 in NHOKs, TECs, and hypopharyngeal carcinoma cells (FaDu) revealed induction of FoxM1B and GRHL2 by the E6 protein but not E7. Both GRHL2 and FoxM1B were strongly induced in the epidermis of HPV-16 E6 transgenic mice and HPVoral squamous cell carcinomas. Ectopic expression of FoxM1B led to acquisition of transformed phenotype in HOK-16B cells. Loss of FoxM1B by lentiviral short hairpin RNA vector or chemical inhibitor led to elimination of tumorigenic characteristics of HOK-16B/BaP-T cells. Luciferase reporter assay revealed that GRHL2 directly bound and regulated the FoxM1B gene promoter activity. Using epithelial-specific Grhl2 conditional knockout mice, we exposed wild-type (WT) and Grhl2 KO mice to 4-nitroquinolin 1-oxide (4-NQO), which led to induction of FoxM1B in the tongue tissues and rampant oral tumor development in the WT mice. However, 4-NQO exposure failed to induce tongue tumors or induction of FoxM1B expression in Grhl2 KO mice. Collectively, these results indicate that HPV-16 induces FoxM1B in part through GRHL2 transcriptional activity and that elevated FoxM1B level is required for oropharyngeal cancer development.
dc.identifier.citationCopyright 2018 Journal of Dental Research. Recommended citation: Chen, W., T. Shimane, S. Kawano, A. Alshaikh, S. Y. Kim, S. H. Chung, R. H. Kim et al. "Human papillomavirus 16 E6 induces FoxM1B in oral keratinocytes through GRHL2." Journal of dental research 97, no. 7 (2018): 795-802. DOI: 10.1177/0022034518756071. URL: Reproduced in accordance with the original publisher's licensing terms and with permission from the author(s).
dc.publisherJournal of Dental Research
dc.subjecthuman papillomavirus
dc.subjectoropharyngeal neoplasms
dc.subjectepithelial cells
dc.subjectgene knockout technique
dc.titleHuman papillomavirus 16 E6 induces FoxM1B in oral keratinocytes through GRHL2


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