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.

• Authors: X Xie, L Piao, B N Bullock, A Smith, T Su, M Zhang, T N Teknos, P S Arora, Q Pan
• Journal: Oncogene (Oncogene) Vol. 33 Issue 8 Pg. 1037-46 (Feb 20 2014) ISSN: 1476-5594 [Electronic] England
• PMID: 23474763 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• E6 protein, Human papillomavirus type 16
• Oncogene Proteins, Viral
• Repressor Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• p300-CBP Transcription Factors
• p300-CBP-associated factor

Topics

• Alphapapillomavirus (isolation & purification)
• Carcinoma, Squamous Cell (metabolism, pathology, virology)
• Head and Neck Neoplasms (metabolism, pathology, virology)
• Humans
• Oncogene Proteins, Viral (metabolism)
• Repressor Proteins (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• p300-CBP Transcription Factors (metabolism)