LncRNA ELF3-AS1 inhibits gastric cancer by forming a negative feedback loop with SNAI2 and regulates ELF3 mRNA stability via interacting with ILF2/ILF3 complex

J Exp Clin Cancer Res. 2022 Dec 2;41(1):332. doi: 10.1186/s13046-022-02541-9.

Abstract

Background: The biological function of lncRNA ELF3-AS1 remains largely unknown in cancers. The cause of SNAI2 overexpression in tumor metastasis remains largely unclear. The molecular mechanisms underlying the high co-expression of antisense lncRNAs and adjacent protein-coding genes remains unclear.

Methods: RNA-seq, CHIP and dual-luciferase reporter assay were performed to identify lncRNAs regulated by SNAI2. MicroRNA-seq and RNA-seq studies were conducted to reveal the biological function of ELF3-AS1 in GC. RNA pulldown and CHIRP assays were conducted to identify the protein that interacts with ELF3-AS1.

Results: A total of 123 lncRNAs were identified to be regulated by SNAI2 in GC by RNA sequencing. The ELF3 gene and antisense lncRNA ELF3-AS1 were both transcriptionally repressed by SNAI2 or SNAI1. Down-regulation of ELF3-AS1 and ELF3 predicted poor prognosis in GC. Nuclear localized lncRNA ELF3-AS1 negatively regulated GC cell cycle progression via suppressing G1/S transition and histone synthesis. ELF3-AS1 mainly inhibited GC metastasis by repressing SNAI2 signaling. Additionally, ELF3-AS1 modulated ELF3 mRNA stability by RNA-RNA interaction. The RNA duplexes formed by ELF3 mRNA and lncRNA ELF3-AS1 directly interacted with the double-stranded RNA (dsRNA) binding protein complex ILF2/ILF3 (NF45/NF90). In turn, the ILF2/ILF3 complex dynamically regulated the expression of ELF3-AS1 and ELF3 by affecting the dsRNA stability.

Conclusions: The SNAI2-ELF3-AS1 feedback loop regulates ELF3 expression at transcriptional and post-transcriptional levels and drives gastric cancer metastasis by maintaining SNAI2 overexpression. The ILF2/ILF3 complex plays a critical role in regulating dsRNA stability. In addition, our work provides a direct evidence that head-to-head antisense lncRNAs can share promoters with neighboring coding genes, which make their expression subject to similar transcriptional regulation, leading to high co-expression.

Keywords: ELF3-AS1; Gastric cancer metastasis; SNAI2 overexpression; Transcriptional regulation; mRNA stability.

MeSH terms

  • DNA-Binding Proteins
  • Down-Regulation
  • Feedback
  • Humans
  • Nuclear Factor 45 Protein
  • Nuclear Factor 90 Proteins / genetics
  • Proto-Oncogene Proteins c-ets
  • RNA Stability
  • RNA, Double-Stranded
  • RNA, Long Noncoding* / genetics
  • Stomach Neoplasms* / genetics
  • Transcription Factors / genetics

Substances

  • RNA, Long Noncoding
  • RNA, Double-Stranded
  • ELF3 protein, human
  • DNA-Binding Proteins
  • Transcription Factors
  • Proto-Oncogene Proteins c-ets
  • ILF3 protein, human
  • Nuclear Factor 90 Proteins
  • ILF2 protein, human
  • Nuclear Factor 45 Protein
  • SNAI2 protein, human