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 models of aneuploidy, we found that aneuploidy confers remarkable resistance to reactive oxygen species (ROS)-mediated cell death. This resistance is a general consequence of aneuploidy, independent of the specific chromosomes gained or lost. Mechanistically, Poly(ADP-Ribose) Polymerase 1 (PARP1) is suppressed 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 promote tumor metastasis while increased PARP1 suppresses it. Through a genome-wide CRISPR 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 that lysosomal dysfunction serves as the upstream mediator of CEBPB activation in aneuploid cells. We propose that aneuploidy-driven CEBPB activation promotes PARP1 suppression, fostering ROS resistance and cancer progression. HighlightsO_LIAneuploidy confers resistance to oxidative stress independent of p53 status, karyotype and cell lineage through inhibition of PARP1 expression and activity C_LIO_LISuppressed PARP1 enhances metastatic potential, while PARP1 restoration suppresses metastatic spread, revealing a novel mechanism linking aneuploidy to cancer progression. C_LIO_LIPARP1 suppression compromises DNA damage repair and cell death to multiple genotoxic stressors, including reactive oxygen species, alkylating agents, and UV radiation. C_LIO_LIA genome-wide CRISPR screen and a CRISPRa screen identifies CEBPB as a critical transcription factor mediating PARP1 regulation and ROS resistance. C_LIO_LINuclear CEBPB increases significantly after aneuploidization in experimental systems and in primary human cancers. C_LI O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/670212v2_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1bf4edforg.highwire.dtl.DTLVardef@d3311eorg.highwire.dtl.DTLVardef@13daf25org.highwire.dtl.DTLVardef@b5e65f_HPS_FORMAT_FIGEXP M_FIG C_FIG