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

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. [Display omitted] •High nuclear expression of caspase-8 occurs in cancers with poor prognosis•Nuclear caspase-8 in cancer cells accumulates in response to treatment•Caspase-8 cleaves USP28 to prevent p53-driven apoptosis of cancer cells•Nuclear caspase-8 promotes progression of wild-type p53 expressing tumors We report an unexpected non-canonical role of caspase-8 in the nucleus of cancer cells. Upon G2/M checkpoint activation, caspase-8 cleaves the de-ubiquitinase USP28, inhibiting its ability to stabilize p53. This leads to a de facto p53 loss, enabling cancer cells to escape p53-dependent apoptosis in favor of mitotic cell division.