Suppression of CPSF6 Enhances Apoptosis Through Alternative Polyadenylation-Mediated Shortening of the VHL 3′UTR in Gastric Cancer Cells

Abstract

Alternative polyadenylation (APA) is an important RNA post-transcriptional process, which can generate diverse mRNA isoforms. Increasing evidence shows that APA is involved in cell self-renewal, development, immunity, and cancer. CPSF6 is one of the core proteins of CFIm complex and can modulate the APA process. Although it has been reported to play oncogenic roles in cancer, the underlying mechanisms remain unclear. The aim of the present study was to characterize CPSF6 in human gastric cancer (GC). We observed that CPSF6 was upregulated in GC. Knockdown of CPSF6 inhibited proliferation and enhanced apoptosis of GC cells both in vitro and in vivo. Global APA site profiling analysis revealed that knockdown of CPSF6 induced widespread 3′UTR shortening of genes in GC cells, including VHL. We also found CPSF6 negatively regulated the expression of VHL through APA and VHL short-3′UTR isoform enhanced apoptosis and inhibited cell growth in GC cells. Our data suggested that CPSF6-induced cell proliferation and inhibition of apoptosis were mediated by the preferential usage of poly(A) in VHL. Our data provide insights into the function of CPSF6 and may imply potential therapeutic targets against GC.

The roles of CPSF6 in proliferation, apoptosis and tumorigenicity of lung adenocarcinoma

“…These findings indicated that CPSF6 participates in cancer development via regulating cell apoptosis. CPSF6 has been found to play an important role in tumorigenesis and progression such as gastric cancer and hepatocellular carcinoma [29,30]. Moreover, pathway analyses showed that the DEGs were involved in multiple cancer-associated pathways, such as TGF-β, mTOR, IGF-1, NF-κB and PTEN pathways in LUAD.…”

Deregulated expression and subcellular localization of CPSF6, a circRNA-binding protein, promote malignant development of esophageal squamous cell carcinoma

“…Previous studies have demonstrated that CPSF6 plays a pro-oncogenic role in several human cancers ( 13 , 18 , 19 ). Herein, we investigated the expression and functions of CPSF6 in ESCC.…”

“…CPSF6 protein, as a regulator of APA, was mainly detected in nucleoplasm and nuclear speckles, and only small amount of that was located in the cytoplasm ( 22 , 23 ). Recent studies have reported that CPSF6 is dysregulated in hepatocellular carcinoma and gastric cancer and functions predominantly in the nucleus at the level of APA regulation to promote tumorigenesis and development ( 13 , 18 ). However, there were no studies reporting the clinical values and functions of cytoplasmic CPSF6 protein.…”

“…CPSF6, as a canonical RBP ( 21 , 23 , 30 , 31 ), plays oncogenic roles in human cancers ( 12 , 13 , 18 ). A few studies have reported that RBPs could dynamically regulate circRNA biogenesis, functions and metabolism ( 32 - 36 ).…”

Editorial: Bioinformatics of Genome Regulation, Volume I

“…Frontiers in Genetics’ publications on human disease biomarkers are continued by the Research Topic “ High-throughput sequencing-based investigation of chronic disease markers and mechanisms ” ( https://www.frontiersin.org/research-topics/21036/high-throughput-sequencing-based-investigation-of-chronic-disease-markers-and-mechanisms ). Thus, Shi et al (2021) studied molecular mechanisms related to alternative polyadenylation in gastric cancer; Chang et al (2021) analyzed platinum-drug resistance mutations in advanced non-small cell lung cancer.…”