CPSF3 as a therapeutic target in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Large-scale RNA sequencing efforts of PDAC tumors have revealed widespread dysregulation of oncogenic gene expression. Recently, we identified widespread alternative polyadenylation (APA) alterations in PDAC patients that are associated with functional changes in both gene and protein expression of growth-promoting genes. We propose that targeting drivers of dysregulated gene expression represents an opportunity to reverse widespread oncogenic activity in transformed cells. Here, we target Cleavage and Polyadenylation Specificity Factor 3 (CPSF3), the 3’ endonuclease that cleaves mRNAs during cleavage and polyadenylation (CPA) and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation of non-transformed pancreatic cells. Additionally, we show that the effect of CPSF3 knockdown and inhibition on 3’-end mRNA processing is distinct. We show that polyadenylation signal (PAS) surrounding motifs of differentially altered APA genes are distinct between CPSF3 knockdown and inhibition. Also, we find that CPSF3 knockdown, but not inhibition, induces CPA complex instability. Moreover, CPSF3 inhibition induces transcriptional read-through in replication-dependent histones preferentially in PDAC cells and reduces core histone mRNA levels. Lastly, JTE-607 destabilizes chromatin structure and arrests cells in the S-phase of the cell cycle. Therefore, CPSF3 represents a potential therapeutic target for the treatment of PDAC.