Targeting CPSF73, the mRNA 3' End Processing Endonuclease, Moves Cancer Cells Away from the Mesenchymal State

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Metastasis is a major cause of cancer mortality and treatment failure.
• Epithelial-mesenchymal transition (EMT) drives cancer cell metastasis.
• Alternative polyadenylation (APA) regulates gene expression, but its role in EMT is unclear.

Purpose of the Study:

• To investigate the role of APA in EMT.
• To examine the effect of CPSF73 inhibition on cancer cell proliferation and EMT.

Main Methods:

• Used JTE-607, a CPSF73 inhibitor, across four cancer cell lines.
• Performed global APA profiling and differential gene expression analysis.
• Utilized antisense oligonucleotides to block specific poly(A) sites.

Main Results:

• CPSF73 inhibition reduced cancer cell proliferation and reversed EMT.
• APA profiling revealed widespread 3'UTR lengthening and intronic PAS suppression.
• Blocking AKT2's proximal PAS led to EMT reversal and reduced cell invasion.

Conclusions:

• APA-mediated 3'UTR lengthening is a key mechanism in EMT reversal.
• Targeting APA or inhibiting CPSF73 presents a potential therapeutic strategy for suppressing metastasis.