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 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.

Hyperthermia Selectively Targets Human Papillomavirus in Cervical Tumors via p53-Dependent Apoptosis

“…Also, targeting E6 resulted into effective killing of HPV-positive cancer cells (35). Targeting of E6, resulting in reactivation of p53, has also been studied in HPV-positive head and neck tumors (36). The main difference between the present study and previous investigations is our use of hyperthermia; although this clinical treatment has been used for decades, the sensitization mechanism in tumor cells is only now starting to unfold (37).…”

HPV: Sex, cancer and a virus

“…In cancers caused by HPV, the virus silences p53 but leaves the gene that produces it intact; by contrast, in HPV-negative cancers, the gene is mutated, probably through exposure to carcinogens, and produces an ineffective version of the protein. This may explain why people with HPV-positive oropharyngeal cancer respond better to treatment: early evidence suggests 6 that chemotherapy or radiation may somehow reactivate p53 in HPV-positive cancers, turning the powerful protein back on to fight the tumour.…”

Meta-analysis of survival in patients with HNSCC discriminates risk depending on combined HPV and p16 status

“…These generally contain wildtype p53 [24] as well as an increased expression of p16, a marker for the oncogenic activity of HR-HPV [24,33]. Proteins derived from the viral oncogenes HPV-E6 and HPV-E7 form complexes with tumor suppressor gene products leading to p53 degradation and pRb inactivation, respectively [70,81]. This is followed by a suppression of apoptosis and initiates a transition to active cell cycling.…”