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KLF13 regulates the differentiation-dependent human papillomavirus life cycle in keratinocytes through STAT5 and IL-8

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Abstract

High-risk strains of human papillomavirus (HPV) are the causative agents of cervical and anogenital cancers and are associated with 5% of all human cancers. Although prophylactic vaccines targeting a subset of HPV types are available, they are ineffective in HPV-infected individuals. Elucidation of the mechanisms controlling HPV replication may allow development of novel anti-HPV therapeutics. Infectious HPV virions are produced during terminal differentiation of host cells. The process of viral maturation requires synergistic interactions between viral and cellular proteins that leads to amplification of the viral genome and expression of late viral genes. Here we show that the transcription factor Kruppel-like factor 13 (KLF13) has a critical role in the HPV life cycle. KLF13 is overexpressed in HPV-positive keratinocytes and cervical cancer cell lines. Expression of KLF13 in normal cervical epithelium is low but increases significantly in cervical intraepithelial neoplasia and invasive squamous cervical cancer. After HPV infection, the E7 protein suppresses ubiquitin ligase FBW7 expression leading to an increase in KLF13 expression. Reduction of KLF13 with short hairpin RNA in differentiating HPV-positive cells resulted in diminished levels of viral gene expression and genome amplification. Knockdown of KLF13 also reduced the level of the transcription factor signal transducer and activator of transcription 5, which led to the downregulation of the ataxia-telangiectasia mutated DNA damage pathway and the chemokine interleukin-8 (IL-8). In addition, neutralization of IL-8 diminished viral genome amplification in differentiating HPV-positive cells. Thus, KLF13 is critical for the activation of the HPV productive life cycle and is likely involved in initiation and progression of cervical cancer.

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Acknowledgements

This work was supported in part by the H Foundation Cancer Research Fund and Robert H Lurie Comprehensive Cancer Center (to W Zhang). We thank Dr Laimonis A Laimins for helpful discussions.

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Author notes

  1. W Zhang and S Hong: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    W Zhang, S Hong, S Cheng, A M Krensky & C Clayberger

  2. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    K P Maniar

  3. Department of Research Biostatistics, Des Moines University, Des Moines, IA, USA

    C Jie

  4. Department of Preventive Medicine and the Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    A W Rademaker

  5. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    A M Krensky

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  1. W Zhang
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Correspondence to C Clayberger.

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Zhang, W., Hong, S., Maniar, K. et al. KLF13 regulates the differentiation-dependent human papillomavirus life cycle in keratinocytes through STAT5 and IL-8. Oncogene 35, 5565–5575 (2016). https://doi.org/10.1038/onc.2016.97

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