IFHNOS edition:5th location:New York, USA date:26-30 July 2014 Oncoforum 2014 location:Leuven, Belgium
The p16/INK4A protein is a principal cyclin-dependent kinase inhibitor that decelerates the cell cycle. Abnormally high levels of p16/INK4A are commonly observed in human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCC). We and others found that p16/INK4A overexpression is associated with improved therapy response and survival of HNSCC patients treated with radiotherapy. However, the functional role of p16/INK4A in HNSCC remains unexplored. Our results implicate p16/INK4A in regulation of homologous recombination (HR)-mediated DNA damage response independently from its role in control of the cell cycle. We found that expression of p16/INK4A dramatically affects radiation sensitivity of HNSCC cells. p16/INK4A overexpression impairs the recruitment of RAD51 to the site of DNA damage in HPV-positive cells by down-regulating of Cyclin D1 protein expression. Consistent with the in vitro findings, immunostaining of HNSCC patient samples revealed that high levels p16/INK4A expression significantly correlated with decreased Cyclin D1 expression. In summary, these findings reveal an unexpected function of p16/INK4A in HR-mediated DNA repair response and imply p16/INK4A status as an independent marker to predict response of HNSCC patients to radiotherapy.