p16INK4a impairs homologous recombination-mediated DNA repair in human papillomavirus-positive head and neck tumors.
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.
Authors' Affiliations: Department of Oncology, Laboratory of Experimental Radiotherapy; Department of Human Genetics, Laboratory for Mechanisms of Cell Transformation; Department of Oncology, Molecular and Digestive Oncology; Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, University of Leuven; VIB Center for the Biology of Disease; Departments of Radiation Oncology; and Pathology, UZ Leuven, Leuven, Belgium.
Rüveyda
R
Dok
Peter
P
Kalev
Evert Jan
EJ
Van Limbergen
Layka Abbasi
LA
Asbagh
Iria
I
Vázquez
Esther
E
Hauben
Anna
A
Sablina
Sandra
S
Nuyts
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000628:therapy / Q000821:virology; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D004249:DNA Damage; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy / Q000821:virology; D006801:Humans; D053208:Kaplan-Meier Estimate; D030361:Papillomavirus Infections / Q000235:genetics* / Q000401:mortality / Q000628:therapy / Q000821:virology; D051135:Rad51 Recombinase / Q000378:metabolism; D011836:Radiation Tolerance; D059767:Recombinational DNA Repair; D016896:Treatment Outcome
C530104:CCND1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019938:Cyclin D1; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C495153:RAD51 protein, human; D051135:Rad51 Recombinase