title: TRIP12 as a mediator of human papillomavirus/p16-related radiation enhancement effects.
abstract: Patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) have better responses to radiotherapy and higher overall survival rates than do patients with HPV-negative HNSCC, but the mechanisms underlying this phenomenon are unknown. p16 is used as a surrogate marker for HPV infection. Our goal was to examine the role of p16 in HPV-related favorable treatment outcomes and to investigate the mechanisms by which p16 may regulate radiosensitivity. HNSCC cells and xenografts (HPV/p16-positive and -negative) were used. p16-overexpressing and small hairpin RNA-knockdown cells were generated, and the effect of p16 on radiosensitivity was determined by clonogenic cell survival and tumor growth delay assays. DNA double-strand breaks (DSBs) were assessed by immunofluorescence analysis of 53BP1 foci; DSB levels were determined by neutral comet assay; western blotting was used to evaluate protein changes; changes in protein half-life were tested with a cycloheximide assay; gene expression was examined by real-time polymerase chain reaction; and data from The Cancer Genome Atlas HNSCC project were analyzed. p16 overexpression led to downregulation of TRIP12, which in turn led to increased RNF168 levels, repressed DNA damage repair (DDR), increased 53BP1 foci and enhanced radioresponsiveness. Inhibition of TRIP12 expression further led to radiosensitization, and overexpression of TRIP12 was associated with poor survival in patients with HPV-positive HNSCC. These findings reveal that p16 participates in radiosensitization through influencing DDR and support the rationale of blocking TRIP12 to improve radiotherapy outcomes.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Molkentine
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Molkentine
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: H
authors.initials: H
authors.lastname: Piao
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: U
authors.initials: U
authors.lastname: Raju
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Valdecanas
authors.affiliation: Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Tailor
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: H D
authors.initials: HD
authors.lastname: Thames
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Buchholz
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Mason
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: K-K
authors.initials: KK
authors.lastname: Ang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Meyn
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: H D
authors.initials: HD
authors.lastname: Skinner
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy* / Q000821:virology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy* / Q000821:virology*; D006801:Humans; D051379:Mice; D027383:Papillomaviridae / Q000235:genetics / Q000502:physiology*; D030361:Papillomavirus Infections / Q000378:metabolism / Q000532:radiotherapy*; D011836:Radiation Tolerance; D011897:Random Allocation; D000077195:Squamous Cell Carcinoma of Head and Neck; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C530813:TRIP12 protein, human; D044767:Ubiquitin-Protein Ligases