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Human papillomavirus (HPV)-related oropharyngeal cancer represents a distinct head and neck squamous cell carcinoma (HNSCC) subpopulation, with improved disease-free and overall survival. In general, HPV-positive HNSCCs express wild-type TP53, which could explain its increased radiosensitivity. However, the molecular mechanisms underlying this higher sensitivity remain elusive. We have previously shown that HPV-related oropharyngeal carcinomas express decreased levels of the NEDD8-activating enzyme 1/amyloid β precursor protein-binding protein 1 (NAE1/APP-BP1) gene. NAE1/APP-BP1 function is required for the NEDDylation of target proteins, and has been shown to be a negative regulator of p53 transcriptional activity. In this study, we addressed the hypothesis that NAE1/APP-BP1 expression levels regulate p53 activity and cell survival upon ionizing irradiation. We used the radiosensitive and naturally HPV16-infected UPCI:SCC90 cell line and the radioresistant and HPV-negative SQ20B cell line as the control. NAE1/APP-BP1 expression levels were modulated with expression constructs and siRNAs. Radiosensitivity was evaluated with clonogenic survival assays. p53 transcriptional activity was measured with a luciferase assay. The overexpression of NAE1/APP-BP1 in UPCI:SCC90 cells resulted in the increased NEDDylation of p53, inhibition of p53 activity and increased cell resistance to ionizing radiation. Conversely, the inhibition of NAE1/APP-BP1 expression in SQ20B cells induced p53-dependent cell death after treatment with X-rays. Taken together, these results indicate that NAE1/APP-BP1 and NEDDylation are invovled in modulating p53 activity and regulating its role in the response of cells to ionizing radiation. Our findings bring new insights in the molecular mechanisms underlying the increased radiosensitivity of HPV-related oropharyngeal tumors. This is of importance, as no reliable and robust predictive biomarkers for tumor response to radiotherapy are currently available. These results also have potential clinical significance, as drugs targeting NAE1/APP-BP1 have recently emerged as a novel therapeutic modality in cancer treatment.

The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation