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

Mol Cell. 2020 Mar 5;77(5):970-984.e7. doi: 10.1016/j.molcel.2019.12.023. Epub 2020 Jan 22.


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.

Keywords: G2/M checkpoint; USP28; apoptosis; cancer; caspase-8; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Cell Nucleus / drug effects
  • Cell Nucleus / enzymology*
  • Cell Nucleus / genetics
  • Cell Nucleus / pathology
  • Cell Proliferation* / drug effects
  • Drug Resistance, Neoplasm
  • Female
  • G2 Phase Cell Cycle Checkpoints* / drug effects
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • MCF-7 Cells
  • Male
  • Neoplasms / drug therapy
  • Neoplasms / enzymology*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • PC-3 Cells
  • Protein Stability
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*


  • Antineoplastic Agents
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • USP28 protein, human
  • Ubiquitin Thiolesterase
  • CASP8 protein, human
  • Caspase 8