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

Xinglong Shi,Jielin Sun,Pengxiao Li,Qiang Zhao,Keshuo Ding,Yani Kang,Sheng Tan

doi:10.3389/fgene.2021.707644

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.

Highlights

Gastric cancer (GC), one of the top five prevalent cancers, is the third leading cause of cancer mortality across the world, owing to its poor prognosis and diagnoses only at advanced stage with median overall survival less than 1 year (Zhang and Zhang, 2017; Smyth et al, 2020)
To explore the clinical relevance of CPSF6 in gastric cancer (GC) patients, we compared the expression of CPSF6 messenger RNA (mRNA), with the RNA-seq data derived from GC (n = 352) and nontumor tissues (n = 32) in The Cancer Genome Atlas (TCGA)
We discovered that the expression of CPSF6 was significantly upregulated in GC tissues (Figure 1B)

Summary

Introduction

Gastric cancer (GC), one of the top five prevalent cancers, is the third leading cause of cancer mortality across the world, owing to its poor prognosis and diagnoses only at advanced stage with median overall survival less than 1 year (Zhang and Zhang, 2017; Smyth et al, 2020). Many predisposing factors, such as Helicobacter pylori infection, age, environmental factors, dietary habits, and so on, assist in the development of GC (Chia and Tan, 2016; Petrovchich and Ford, 2016). The regulation of GC development and progression seems complex; a deeper understanding of the pathogenesis mechanism of GC at the molecular level may be beneficial to identify potential therapeutic targets.

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