C/EBPβ-mediated PARP1 Suppression Drives Tumor Progression of Aneuploid Cells

Aneuploidy--defined as gains and losses of chromosomes--is frequently observed in cancer and has been implicated in promoting tumor progression and metastasis. However, the molecular mechanisms underlying this phenomenon remain poorly understood. By generating new in vitro and in vivo models of aneuploidy, we found that aneuploidy confers remarkable resistance to reactive oxygen species (ROS)-mediated cell death. This is a general consequence of aneuploidy, independent of the specific chromosomes gained or lost. Mechanistically, aneuploidy-induced resistance to cell death results from suppressed Poly(ADP-Ribose) Polymerase 1 (PARP1) in aneuploid cells, which inhibits PARP1-mediated cell death after ROS (parthanatos). We validated aneuploidy-associated PARP1 suppression across 15 cell models and human tumors, with pronounced effects in metastatic tumors. Importantly, decreased PARP1 levels in aneuploid cells promote tumor metastasis and vice versa. Through genome-wide CRISPR screen, a focused CRISPRa screen and functional validation, we identified the transcription factor CCAAT/enhancer-binding protein beta (CEBPB) as a critical mediator of PARP1 downregulation and ROS resistance in aneuploid cells. Furthermore, we found lysosomal dysfunction as the upstream mediator of CEBPB activation in aneuploid cells. We propose that during tumorigenesis, aneuploidy-driven CEBPB activation promotes PARP1 suppression fostering ROS resistance and cancer progression.