Abstract PO-023: The AP-1 transcription factor component, JunB, regulates the expression of HPV genes in head and neck cancer

• Published in: Clinical cancer research 2023-09, Vol.29 (18_Supplement), p.PO-023-PO-023
• Main Authors: Rehmani, Hina, Isaeva, Natalia, Schrank, Travis P., Yarbrough, Wendell G.
• Format: Article
• Language: English
• ISSN: 1557-3265; 1557-3265
• DOI: 10.1158/1557-3265.AACRAHNS23-PO-023

Within head and neck squamous cell carcinoma (HNSCC), those induced by the human papillomavirus (HPV+) have a more hypermethylated genome compared to those that are negative (HPV-). Therefore, our lab explored the usage of the demethylating agent 5-azacytidine (5-aza), an FDA-approved drug for the treatment of myelodysplasia and acute myeloid leukemia. Repurposing FDA-approved drugs is a strategic way to quickly provide patients with secondary therapeutic options, especially since the incidence of HPV+ HNSCC is now considered an epidemic in the US and Western Europe. Additionally, initial therapy for patients is aggressive leading to adverse, lifelong side effects. Despite having a higher cure rate than HPV-HNSCC, the recurrence rate is still approximately 30% for HPV+ HNSCC. Our lab has found that HPV+ HNSCC cells are more sensitive than HPV- cells to 5-aza as low doses of 5-aza delayed HPV+ xenograft tumor growth and 5-aza-treated HPV+ tumor samples from patients treated in a window trial had increased cell death. Despite demethylation inducing an active, open chromatin conformation, we also observed a marked downregulation of HPV genes expression after 5-aza. Decreased HPV E6 expression, followed by reactivation of tumor suppressor p53, induced p53-dependent apoptosis in HPV+ HNSCC. This decreased expression of HPV genes is an essential component of 5-aza-associated toxicity toward HPV+ HNSCC. Our lab has recently explored the molecular mechanisms of 5-aza on HPV+ HNSCC. We found that 5-aza transcriptionally downregulated the expression of HPV genes, including oncogenes E6 and E7. Microarray studies show marked downregulation of the proto-oncogene JunB, a component of the transcription factor AP-1 (Activator Protein 1) after 5-aza treatment. Experimental deletion of JunB inhibited oncogenes E6 and E7 and restored p53 but also indicated that untreated HPV+ HNSCCs depend on JunB for clonogenic growth. Through this study, we have identified a novel dependency on JunB in HPV+ HNSCC and revealed a new rational target that is desperately needed to treat recurrent/metastatic patients and decrease the toxicity associated with current treatment. Citation Format: Hina Rehmani, Natalia Isaeva, Travis P. Schrank, Wendell G. Yarbrough. The AP-1 transcription factor component, JunB, regulates the expression of HPV genes in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Transla