Targeting HPV16 E6-p300 interaction reactivates p53 and inhibits the tumorigenicity of HPV-positive head and neck squamous cell carcinoma
| Autor: | Longzhu Piao, Paramjit S. Arora, Ashley Smith, Quintin Pan, Brooke N. Bullock, Theodoros N. Teknos, Xiujie Xie, Tizhi Su, Manchao Zhang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
p53
Cancer Research anti-cancer therapeutics Population Cell p300 P300-CBP Transcription Factors Biology Alphapapillomavirus Molecular oncology Article Growth factor receptor Genetics medicine Humans p300-CBP Transcription Factors education human papillomavirus Molecular Biology education.field_of_study Cancer Oncogene Proteins Viral Cell cycle medicine.disease Head and neck squamous-cell carcinoma 3. Good health Repressor Proteins stomatognathic diseases medicine.anatomical_structure Head and Neck Neoplasms Cancer research Carcinoma Squamous Cell head and neck cancer Tumor Suppressor Protein p53 |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | 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 may be 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 anti-cancer 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 anti-cancer 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. |
| Databáze: | OpenAIRE |
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