3'UTR-directed, kinase-proximal mRNA decay inhibits C/EBPβ phosphorylation/activation to suppress senescence in tumor cells.

C/EBPβ regulates oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP) through activation by ERK1/2 and CK2. In tumor cells, C/EBPβ activity is suppressed by its 3'UTR via a mechanism termed 3'UTR regulation of protein activity (UPA), which spatially segregates CEBPB transcripts from kinase-rich perinuclear endosomes. Here, we identify kinase-proximal mRNA decay as the underlying mechanism. The mRNA decay factors UPF1 and STAU1/2 localize to perinuclear endosomes and promote degradation of CEBPB transcripts, thereby preventing C/EBPβ phosphorylation and activation. Disruption of this pathway restores C/EBPβ activity and induces senescence. In vivo, deletion of a G/U-rich regulatory element (GRE) in the 3'UTR impairs the progression of Kras-driven lung tumors and biases cells toward an AT2-like differentiation state with reduced EMT-associated transcriptional reprogramming. RAS-expressing GRE Δ/Δ fibroblasts show enhanced OIS that requires upregulation of the pro-senescent cytokine S100a9. These findings identify perinuclear mRNA decay as a mechanism suppressing C/EBPβ activity and senescence in cancer.