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

Abstract

Abstract 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 Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-023.