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.

中文翻译：

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癌细胞利用核 Caspase-8 通过切割 USP28 来克服 p53 依赖性 G2/M 检查点。

胞浆 caspase-8 是死亡受体信号传导的介质。虽然 caspase-8 表达在某些肿瘤中缺失，但在其他肿瘤中表达增加，表明 caspase-8 在癌症中具有条件性促生存功能。在这里，我们证明肿瘤细胞利用 DNA 损伤诱导的核 caspase-8 来覆盖 p53 依赖性 G2/M 细胞周期检查点。在多种人类癌症中，Caspase-8 表达上调并定位于细胞核，与治疗耐药性和不良临床结果相关。caspase-8 的耗竭会导致 G2/M 期停滞、p53 稳定并诱导肿瘤细胞中 p53 依赖性内在凋亡。在细胞核中，caspase-8 裂解泛素特异性肽酶 28 (USP28) 并使其失活，从而防止 USP28 去泛素化并稳定野生型 p53。这导致事实上的 p53 蛋白丢失，将细胞命运从细胞凋亡转变为有丝分裂。总之，我们的工作确定了癌细胞利用 caspase-8 超越 p53 依赖性 G2/M 细胞周期检查点的非典型作用。