QKI5-mediated alternative splicing of the histone variant macroH2A1 regulates gastric carcinogenesis.

Feng Li,Jingyi Hui,Jingnan Pi,Ping Yi,Lanfang Li,Aihua Liang,Jia Yu,Fang Wang

doi:10.18632/oncotarget.8739

Abstract

Alternative pre-mRNA splicing is a key mechanism for increasing proteomic diversity and modulating gene expression. Emerging evidence indicated that the splicing program is frequently dysregulated during tumorigenesis. Cancer cells produce protein isoforms that can promote growth and survival. The RNA-binding protein QKI5 is a critical regulator of alternative splicing in expanding lists of primary human tumors and tumor cell lines. However, its biological role and regulatory mechanism are poorly defined in gastric cancer (GC) development and progression. In this study, we demonstrated that the downregulation of QKI5 was associated with pTNM stage and pM state of GC patients. Re-introduction of QKI5 could inhibit GC cell proliferation, migration, and invasion in vitro and in vivo, which might be due to the altered splicing pattern of macroH2A1 pre-mRNA, leading to the accumulation of macroH2A1.1 isoform. Furthermore, QKI5 could inhibit cyclin L1 expression via promoting macroH2A1.1 production. Thus, this study identified a novel regulatory axis involved in gastric tumorigenesis and provided a new strategy for GC therapy.

Highlights

Alternative splicing generates multiple different mRNAs and downstream proteins from a single gene through the inclusion or exclusion of specific exons [1, 2]
Immunohistochemistry revealed that macroH2A1.1 staining was significantly decreased in gastric cancer (GC) tissues (Figure 5F). All these findings indicated that the tumor suppressor role was specific to macroH2A1.1 in GC cells, which was consistent with its alternative splicing regulator QKI5
Many oncogenes or tumor suppressors have been identified as key regulators in GC tumorigenesis, almost no commonly accepted biomarkers or therapy targets have been established to facilitate the comprehensive management of patients [39, 40]

Summary

Introduction

Alternative splicing generates multiple different mRNAs and downstream proteins from a single gene through the inclusion or exclusion of specific exons [1, 2]. This process occurs in 95% of all multi-exonic genes, and dysregulation of splicing underlies many human diseases, including cancer. The ability to commandeer alternative splicing is beneficial to cancer cells if early developmental stage isoforms critical for proliferation or apoptosis are expressed. Metabolic pathways are frequently altered in cancer, as the Warburg effect, a shift from oxidative phosphorylation to aerobic glycolysis, is partly driven by alternative splicing of the pyruvate kinase M (PKM) gene [8]. In the alternative splicing of PKM mRNA, exons 9 and 10 are mutually exclusive, resulting in the adult isoform PKM1

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Conclusion