Targeting hpv16 e6-p300 interaction reactivates p53 and inhibits the tumorigenicity of hpv-positive head and neck squamous cell carcinoma

ABSTRACT The incidence of human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) has rapidly increased over the past 30 years, prompting the suggestion that an

epidemic maybe on the horizon. Therefore, there is a clinical need to develop alternate therapeutic strategies to manage the growing number of HPV-positive HNSCC patients. High-risk HPV E6

inactivates p53 through two distinct mechanisms; association with E6AP to degrade p53 and association with p300 to block p300-mediated p53 acetylation and activation. In this study, we

determined if targeting the E6-p300 interaction is an effective approach to reactivate p53 in HPV-positive HNSCC. Ectopic expression of the CH1 domain of p300 in HPV-positive HNSCC blocks

the association between E6 and p300, increases total and acetylated p53 levels and enhances p53 transcriptional activity. Moreover, expression of p21, miR-34a and miR-200c are increased,

demonstrating functional p53 reactivation. CH1 overexpression in HPV-positive HNSCC has a global anticancer effect resulting in a decrease in cell proliferation and clonogenic survival and

an increase in apoptosis. The _in vivo_ tumor-initiating ability of HPV-positive HNSCC is severely compromised with CH1 overexpression, in part through a reduction in the cancer-initiating

cell population. A novel small-molecule CH1 inhibitor, CH1iB, reactivates p53 and potentiates the anticancer activity of cis-platinum in HPV-positive HNSCC cells. Our work shows that

CH1-domain inhibitors represent a novel class of p53-reactivation therapeutics for managing HPV-positive HNSCC patients. Access through your institution Buy or subscribe This is a preview of

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surrogate approach. _Nat Protoc_ 2010; 5: 1857–1865. Article  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported in part by National

Institutes of Health grants R01CA135096 (to QP) and R01GM073943 (to PSA); Mary E. and John W. Alford Cancer Research Endowment Fund; The Michelle Theado Memorial Grant from the Joan Bisesi

Fund for Head and Neck Oncology Research; and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Ohio State University Comprehensive Cancer Center. AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS * Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA X Xie, L Piao, A Smith, T Su, M Zhang, T N

Teknos & Q Pan * Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA X Xie, L Piao, A

Smith, T Su, M Zhang, T N Teknos & Q Pan * Department of Chemistry, New York University, New York, NY, USA B N Bullock & P S Arora Authors * X Xie View author publications You can

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ADDITIONAL INFORMATION Supplementary Information accompanies the paper on the Oncogene website SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURE S1 (JPG 277 KB) SUPPLEMENTARY TABLE S1 AND

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Targeting HPV16 E6-p300 interaction reactivates p53 and inhibits the tumorigenicity of HPV-positive head and neck squamous cell carcinoma. _Oncogene_ 33, 1037–1046 (2014).

https://doi.org/10.1038/onc.2013.25 Download citation * Received: 03 July 2012 * Revised: 17 December 2012 * Accepted: 27 December 2012 * Published: 11 March 2013 * Issue Date: 20 February

2014 * DOI: https://doi.org/10.1038/onc.2013.25 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is

not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * human papillomavirus * anticancer therapeutics *

p53 * p300 * head and neck cancer