24. Januar 2020

Joint research paper on a non-canonical function of caspase-8 published in Molecular Cell.

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

Ines Müller, Elwira Strozyk, Sebastian Schindler, Stefan Beissert, Htoo Zarni Oo, Thomas Sauter, Philippe Lucarelli, Sebastian Raeth, Angelika Hausser, Nader Al Nakouzi, Ladan Fazli, Martin E. Gleave, He Liu, Hans-Uwe Simon, Henning Walczak, Douglas R. Green, Jiri Bartek, Mads Daugaard, Dagmar Kulms

Abstract

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.

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