摘要：SummaryCleavage by the endonuclease CPSF73 and polyadenylation of nascent RNA is an essential step in co-transcriptional mRNA maturation. Recent work has surprisingly identified CPSF73 as a promising drug target for inhibiting the growth of specific cancers, triggering further studies on understanding CPSF73 regulation and functions in cells. Here, we report that a HECT-like E3 ligase, UBE3D, participates in stabilizing CPFS73 protein by preventing its ubiquitin-mediated degradation by the proteasome. Depletion ofUBE3Dleads to CPSF73 downregulation, a pre-mRNA cleavage defect, and dysregulated gene expression in cells. UBE3D dysfunction or chemical inactivation of CPSF73 inhibited migration and invasion as well as stem cell renewal phenotypesin vitroin triple-negative breast cancer cells. In addition, genetic overexpression of CPSF73 promoted breast cancer stemness and knocking down CPSF73 inhibited stem cell renewal properties. Together, our findings indicate that targeting the pre-mRNA processing nuclease CPSF73 has potential for breast cancer therapy.Graphical abstractDisplay OmittedHighlights•UBE3D regulates CPSF73 in a conserved way as is found for its yeast homolog•UBE3D stabilizes CPSF73 by protecting it from ubiquitin-mediated degradation•UBE3D regulates breast cancer cell migration and invasion through CPSF73•The level of CPSF73 correlates with breast cancer cell self-renewal propertiesBiological sciences; Molecular biology; Cell biology; Cancer
