Back
Cancer Cells Employ Nuclear Caspase-8 to Overcome the p53-Dependent G2/M Checkpoint through Cleavage of USP28.
Journal article

Cancer Cells Employ Nuclear Caspase-8 to Overcome the p53-Dependent G2/M Checkpoint through Cleavage of USP28.

  • Müller I Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden 01307, Germany; Center for Regenerative Therapies Dresden, TU-Dresden, Dresden 01307, Germany.
  • Strozyk E Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden 01307, Germany; Center for Regenerative Therapies Dresden, TU-Dresden, Dresden 01307, Germany.
  • Schindler S Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden 01307, Germany; Center for Regenerative Therapies Dresden, TU-Dresden, Dresden 01307, Germany.
  • Beissert S Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden 01307, Germany.
  • Oo HZ Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
  • Sauter T Systems Biology, Life Science Research Unit, University of Luxembourg, 1511 Luxembourg, Luxembourg.
  • Lucarelli P Systems Biology, Life Science Research Unit, University of Luxembourg, 1511 Luxembourg, Luxembourg.
  • Raeth S Institute of Cell Biology and Immunology and Stuttgart Research Centre Systems Biology, University of Stuttgart, Stuttgart 70569, Germany.
  • Hausser A Institute of Cell Biology and Immunology and Stuttgart Research Centre Systems Biology, University of Stuttgart, Stuttgart 70569, Germany.
  • Al Nakouzi N Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
  • Fazli L Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
  • Gleave ME Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
  • Liu H Institute of Pharmacology, University of Bern, Bern 3010, Switzerland.
  • Simon HU Institute of Pharmacology, University of Bern, Bern 3010, Switzerland.
  • Walczak H Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
  • Green DR Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • Bartek J Danish Cancer Society Research Center, Copenhagen 2100, Denmark; Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 171 77, Sweden.
  • Daugaard M Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
  • Kulms D Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden 01307, Germany; Center for Regenerative Therapies Dresden, TU-Dresden, Dresden 01307, Germany. Electronic address: dagmar.kulms@uniklinikum-dresden.de.
Show more…
  • 2020-01-27
Published in:
  • Molecular cell. - 2020
G2/M checkpoint
USP28
apoptosis
cancer
caspase-8
p53
Antineoplastic Agents
Apoptosis
Caspase 8
Cell Nucleus
Cell Proliferation
Drug Resistance, Neoplasm
Female
G2 Phase Cell Cycle Checkpoints
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
HCT116 Cells
HeLa Cells
Humans
MCF-7 Cells
Male
Neoplasms
PC-3 Cells
Protein Stability
Signal Transduction
Tumor Cells, Cultured
Tumor Suppressor Protein p53
Ubiquitin Thiolesterase
English Cytosolic caspase-8 is a mediator of death receptor signaling. While caspase-8 expression is lost in some tumors, it is increased in others, indicating a conditional pro-survival function of caspase-8 in cancer. Here, we show that tumor cells employ DNA-damage-induced nuclear caspase-8 to override the p53-dependent G2/M cell-cycle checkpoint. Caspase-8 is upregulated and localized to the nucleus in multiple human cancers, correlating with treatment resistance and poor clinical outcome. Depletion of caspase-8 causes G2/M arrest, stabilization of p53, and induction of p53-dependent intrinsic apoptosis in tumor cells. In the nucleus, caspase-8 cleaves and inactivates the ubiquitin-specific peptidase 28 (USP28), preventing USP28 from de-ubiquitinating and stabilizing wild-type p53. This results in de facto p53 protein loss, switching cell fate from apoptosis toward mitosis. In summary, our work identifies a non-canonical role of caspase-8 exploited by cancer cells to override the p53-dependent G2/M cell-cycle checkpoint.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/279174
Statistics
Document views: 43 File downloads: