Abstract 5722: Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration and invasion

Abstract

Abstract Cleavage by the endonuclease CPSF73 and polyadenylation of nascent RNA is an essential step in co-transcriptional mRNA maturation, and abnormal poly(A) site choices have been associated with human diseases, including cancer. Recent work has identified CPSF73 as a promising drug target for inhibiting the growth of specific cancers, and higher level of CPSF73 correlates to poor survival in breast cancer patients. However, our understanding of the regulation of CPSF73 is still at an early stage. 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 of UBE3D in both non-cancer cells and cancer cells leads to CPSF73 downregulation, a pre-mRNA cleavage defect and dysregulated gene expression. UBE3D dysfunction or chemical inactivation of CPFS73 inhibited migration and invasion as well as stem cell renewal phenotypes in vitro in triple negative breast cancer cells. In addition, genetic overexpression of CPSF73 promoted breast cancer stemness and knocking down of CPSF73 inhibited stem cell renewal property. Together, our findings indicate that targeting the pre-mRNA processing nuclease CPSF73 has potential for breast cancer therapy. This work was supported by the NSF grant NS0224 to C. Moore and the NIH grant R01 GM101010-01A1 to C. Moore. Citation Format: Huiyun Liu, Daniel Heller-Trulli, Claire Moore. Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5722.