title: 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.affiliation: 1] Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA [2] Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Xie
authors.affiliation: 1] Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA [2] Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: L
authors.initials: L
authors.lastname: Piao
authors.affiliation: Department of Chemistry, New York University, New York, NY, USA.
authors.forename: B N
authors.initials: BN
authors.lastname: Bullock
authors.affiliation: 1] Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA [2] Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Smith
authors.affiliation: 1] Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA [2] Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: Su
authors.affiliation: 1] Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA [2] Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: 1] Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA [2] Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: T N
authors.initials: TN
authors.lastname: Teknos
authors.affiliation: Department of Chemistry, New York University, New York, NY, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Arora
authors.affiliation: 1] Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA [2] Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Pan
mesh_terms: D052685:Alphapapillomavirus / Q000302:isolation & purification*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C068651:E6 protein, Human papillomavirus type 16; C495901:TP53 protein, human