p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

Abstract

The p16INK4a protein is a principal cyclin-dependent kinase inhibitor that decelerates the cell cycle. Abnormally high levels of p16INK4a are commonly observed in human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCC). We and others found that p16INK4a overexpression is associated with improved therapy response and survival of patients with HNSCC treated with radiotherapy. However, the functional role of p16INK4a in HNSCC remains unexplored. Our results implicate p16INK4a in regulation of homologous recombination-mediated DNA damage response independently from its role in control of the cell cycle. We found that expression of p16INK4a dramatically affects radiation sensitivity of HNSCC cells. p16INK4a overexpression impairs the recruitment of RAD51 to the site of DNA damage in HPV-positive cells by downregulating of cyclin D1 protein expression. Consistent with the in vitro findings, immunostaining of HNSCC patient samples revealed that high levels p16INK4a expression significantly correlated with decreased cyclin D1 expression. In summary, these findings reveal an unexpected function of p16INK4a in homologous recombination-mediated DNA repair response and imply p16INK4a status as an independent marker to predict response of patients with HNSCC to radiotherapy. Cancer Res; 74(6);

G2-checkpoint targeting and radiosensitization of HPV/p16-positive HNSCC cells through the inhibition of Chk1 and Wee1

“…Hence, additional factors are likely to be involved. One possible mechanism could be the inhibition of homologous recombination, though, UPCI-SCC-154 cells are reportedly deficient for HR due to the high expression of p16 and/ or lack of expression of BRCA2 [23,24]. Further studies are necessary to identify additional factors contributing to radiosensitization and to identify predictive biomarkers.…”

Efficacy and mucosal toxicity of concomitant chemo-radiotherapy in patients with locally-advanced squamous cell carcinoma of the head-and-neck in the light of a novel mathematical model

“…For this reason it has been included as prognostic factor in the MVA, by extending to the new population the results reported by Calais et al (1998). In this regard, emerging evidence supports HPV association with better response and survival in HNSCC patients treated with RT (Dok et al, 2014), suggesting the intriguing role of p16INK4a status as an independent predictive marker. However, the mechanism triggering this biological effect still has to be fully understood and it is not taken into account in our model.…”

Evaluation of Toxicity Profile and Prognosis of Treatment of Hpv Associated Head and Neck Squamous Cell Carcinoma (HNSCC), with Chemoradiotherapy

“…the study also showed a trend towards improved treatment outcome for patients with HPV positive tumors. In the analysis of association of tumor p16INK4A expression with therapeutic response in a prospectively collected cohort of patients with HNSCC treated with radiotherapy alone, showed that tumor cell expression of p16INK4A in this group of patients is associated with markedly improved treatment response and survival and that p16INK4A expression status is an independent prognostic factor for both outcomes 14 .…”