Targeting HPV16 E6-p300 interaction reactivates p53 and inhibits the tumorigenicity of HPV-positive head and neck squamous cell carcinoma

X. Xie, L. Piao, B. N. Bullock, A. Smith, T. Su, M. Zhang, T. N. Teknos, Paramjit Arora, Q. Pan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1037-1046
Number of pages10
JournalOncogene
Volume33
Issue number8
DOIs
StatePublished - Feb 20 2014

Fingerprint

Carcinoma, squamous cell of head and neck
Acetylation
Cisplatin
Neoplasms
Cell Proliferation
Apoptosis
Survival
Incidence
Therapeutics
Population
Ectopic Gene Expression

Keywords

  • Anticancer therapeutics
  • Head and neck cancer
  • Human papillomavirus
  • p300
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Targeting HPV16 E6-p300 interaction reactivates p53 and inhibits the tumorigenicity of HPV-positive head and neck squamous cell carcinoma. / Xie, X.; Piao, L.; Bullock, B. N.; Smith, A.; Su, T.; Zhang, M.; Teknos, T. N.; Arora, Paramjit; Pan, Q.

In: Oncogene, Vol. 33, No. 8, 20.02.2014, p. 1037-1046.

Research output: Contribution to journalArticle

Xie, X. ; Piao, L. ; Bullock, B. N. ; Smith, A. ; Su, T. ; Zhang, M. ; Teknos, T. N. ; Arora, Paramjit ; Pan, Q. / Targeting HPV16 E6-p300 interaction reactivates p53 and inhibits the tumorigenicity of HPV-positive head and neck squamous cell carcinoma. In: Oncogene. 2014 ; Vol. 33, No. 8. pp. 1037-1046.
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