Abstract 68: Functional interactions of HPV and PARP-1 in head and neck cancer

Abstract

Abstract Though the overall incidence of head and neck cancer has been declining over the last several decades, there has been a concomitant and worrisome rise in human-papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). HPV infection is a necessary but not sufficient condition for cancer development. Unlike in cervical cancer, where several co-factors including smoking and co-infection with other agents are well established, how HPV drives malignant transformation in head and neck cancer and which cellular factors are required are not well characterized. Recent evidence from our group has shown that poly (ADP-ribose) polymerase-1 (PARP-1) is overexpressed and overactive in HPV-positive (HPV(+)), but not HPV-negative (HPV(-)), oropharyngeal squamous cell carcinoma (OPSCC). The significance of PARP-1 overexpression and hyperactivation in cancer is only beginning to emerge. High levels of PARP-1 are found in a fraction of hepatocellular and breast cancers and correlate with poor prognosis. Recently, PARP-1 was implicated in prostate cancer progression. This study explores the role of PARP-1 in HPV infection and HNSCC carcinogenesis. Biochemical methods were used to determine PARP activity in vitro, in head and neck tumors, and during infection with HPV16 pseudovirus (PsV) or overexpression of HPV16 proteins in epithelial cells. The response to PARP inhibition was evaluated with clonogenic survival assays. HPV L1 mRNA in HNSCC was detected using quantitative real-time PCR and HPV L1 protein levels were determined by immunohistochemistry. Here, we show that the HPV16 major capsid protein L1 directly binds PARP-1 and activates poly(ADP-ribosyl)ation in the absence of DNA damage in vitro and in HPV(-) cells. Using PARP-1 knockout cells, we found that PARP-1 expression and enzymatic activity supports initial HPV infection. Furthermore, HPV(-) cells were sensitized to PARP inhibition both after L1 overexpression and after infection with HPV16 PsV particles. In conclusion, we report functional interactions between the viral capsid and cellular protein, signifying a vital role played by PARP-1 in HPV infection and carcinogenesis. Importantly, our data provide a mechanistic explanation for pharmacological PARP inhibition as an intriguing therapeutic opportunity for HPV(+) head and neck cancers. Citation Format: Cyril S. Gary, Michael Hajek, Asel Biktasova, Andrew Sewell, Yarbrough G. Wendell, Natalia Issaeva. Functional interactions of HPV and PARP-1 in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 68.