title: ΔNp63 activates the Fanconi anemia DNA repair pathway and limits the efficacy of cisplatin treatment in squamous cell carcinoma.
abstract: TP63, a member of the p53 gene family gene, encodes the ΔNp63 protein and is one of the most frequently amplified genes in squamous cell carcinomas (SCC) of the head and neck (HNSCC) and lungs (LUSC). Using an epiallelic series of siRNAs with intrinsically different knockdown abilities, we show that the complete loss of ΔNp63 strongly impaired cell proliferation, whereas partial ΔNp63 depletion rendered cells hypersensitive to cisplatin accompanied by an accumulation of DNA damage. Expression profiling revealed wide-spread transcriptional regulation of DNA repair genes and in particular Fanconi anemia (FA) pathway components such as FANCD2 and RAD18 - known to be crucial for the repair of cisplatin-induced interstrand crosslinks. In SCC patients ΔNp63 levels significantly correlate with FANCD2 and RAD18 expression confirming ΔNp63 as a key activator of the FA pathway in vivo Mechanistically, ΔNp63 bound an upstream enhancer of FANCD2 inactive in primary keratinocytes but aberrantly activated by ΔNp63 in SCC. Consistently, depletion of FANCD2 sensitized to cisplatin similar to depletion of ΔNp63. Together, our results demonstrate that ΔNp63 directly activates the FA pathway in SCC and limits the efficacy of cisplatin treatment. Targeting ΔNp63 therefore would not only inhibit SCC proliferation but also sensitize tumors to chemotherapy.
authors.affiliation: Institute of Molecular Oncology, Philipps-University Marburg, 35043 Marburg, Germany.
authors.forename: Anne Catherine
authors.initials: AC
authors.lastname: Bretz
authors.affiliation: Institute of Molecular Oncology, Philipps-University Marburg, 35043 Marburg, Germany.
authors.forename: Miriam P
authors.initials: MP
authors.lastname: Gittler
authors.affiliation: Institute of Molecular Oncology, Philipps-University Marburg, 35043 Marburg, Germany.
authors.forename: Joël P
authors.initials: JP
authors.lastname: Charles
authors.affiliation: Institute of Molecular Oncology, Philipps-University Marburg, 35043 Marburg, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Gremke
authors.affiliation: Institute of Molecular Oncology, Philipps-University Marburg, 35043 Marburg, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Eckhardt
authors.affiliation: Institute of Molecular Oncology, Philipps-University Marburg, 35043 Marburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Mernberger
authors.affiliation: Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital Giessen and Marburg, Philipps-University, 35033 Marburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Mandic
authors.affiliation: Institute of Cell Biology, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Thomale
authors.affiliation: Genomics Core Facility, Philipps-University Marburg, 35043 Marburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nist
authors.affiliation: Institute of Molecular Oncology, Philipps-University Marburg, 35043 Marburg, Germany Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research (DZL), 35043 Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wanzel
authors.affiliation: Institute of Molecular Oncology, Philipps-University Marburg, 35043 Marburg, Germany Genomics Core Facility, Philipps-University Marburg, 35043 Marburg, Germany Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research (DZL), 35043 Marburg, Germany thorsten.stiewe@uni-marburg.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stiewe
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D002945:Cisplatin / Q000627:therapeutic use*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004742:Enhancer Elements, Genetic; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000378:metabolism* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; C485954:RAD18 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D002945:Cisplatin
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