Science and Research

DeltaNp63 activates the Fanconi anemia DNA repair pathway and limits the efficacy of cisplatin treatment in squamous cell carcinoma

TP63, a member of the p53 gene family gene, encodes the DeltaNp63 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 DeltaNp63 strongly impaired cell proliferation, whereas partial DeltaNp63 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 DeltaNp63 levels significantly correlate with FANCD2 and RAD18 expression confirming DeltaNp63 as a key activator of the FA pathway in vivo Mechanistically, DeltaNp63 bound an upstream enhancer of FANCD2 inactive in primary keratinocytes but aberrantly activated by DeltaNp63 in SCC. Consistently, depletion of FANCD2 sensitized to cisplatin similar to depletion of DeltaNp63. Together, our results demonstrate that DeltaNp63 directly activates the FA pathway in SCC and limits the efficacy of cisplatin treatment. Targeting DeltaNp63 therefore would not only inhibit SCC proliferation but also sensitize tumors to chemotherapy.

  • Bretz, A. C.; Gittler, M. P.; Charles, J. P.; Gremke, N.; Eckhardt, I.; Mernberger, M.; Mandic, R.; Thomale, J.; Nist, A.; Wanzel, M.; Stiewe, T.

Keywords

  • Antineoplastic Agents/*therapeutic use
  • Carcinoma, Squamous Cell/drug therapy/*genetics/metabolism/pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Cisplatin/*therapeutic use
  • *DNA Repair
  • DNA-Binding Proteins/metabolism
  • Drug Resistance, Neoplasm
  • Enhancer Elements, Genetic
  • Fanconi Anemia Complementation Group D2 Protein/genetics/metabolism
  • Humans
  • Transcription Factors/*metabolism/physiology
  • Transcriptional Activation
  • Tumor Suppressor Proteins/*metabolism/physiology
  • Ubiquitin-Protein Ligases/metabolism
Publication details
DOI: 10.1093/nar/gkw036
Journal: Nucleic acids research
Pages: 3204-18 
Number: 7
Work Type: Original
Location: UGMLC
Disease Area: General Lung and Other
Partner / Member: UMR
Access-Number: 26819410
See publication on PubMed

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