LncRNA GClnc1 Promotes Gastric Carcinogenesis and May Act as a Modular Scaffold of WDR5 and KAT2A Complexes to Specify the Histone Modification Pattern

Cancer Discov. 2016 Jul;6(7):784-801. doi: 10.1158/2159-8290.CD-15-0921. Epub 2016 May 4.

Abstract

Long noncoding RNAs (lncRNA) play a role in carcinogenesis. However, the function of lncRNAs in human gastric cancer remains largely unknown. In this study, we identified a novel lncRNA, GClnc1, which was upregulated and associated with tumorigenesis, tumor size, metastasis, and poor prognosis in gastric cancer. GClnc1 affected gastric cancer cell proliferation, invasiveness, and metastasis in multiple gastric cancer models. Mechanistically, GClnc1 bound WDR5 (a key component of histone methyltransferase complex) and KAT2A histone acetyltransferase, acted as a modular scaffold of WDR5 and KAT2A complexes, coordinated their localization, specified the histone modification pattern on the target genes, including SOD2, and consequently altered gastric cancer cell biology. Thus, GClnc1 is mechanistically, functionally, and clinically oncogenic in gastric cancer. Targeting GClnc1 and its pathway may be meaningful for treating patients with gastric cancer.

Significance: This report documents a novel lncRNA, GClnc1, which may act as a scaffold to recruit the WDR5 and KAT2A complex and modify the transcription of target genes. This study reveals that GClnc1 is an oncogenic lncRNA in human gastric cancer. Cancer Discov; 6(7); 784-801. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Chromatin Immunoprecipitation
  • Cluster Analysis
  • Computational Biology
  • Disease Models, Animal
  • Disease Progression
  • Epigenesis, Genetic
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Heterografts
  • High-Throughput Nucleotide Sequencing
  • Histone Acetyltransferases / metabolism*
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Models, Biological
  • Protein Binding
  • RNA, Long Noncoding / genetics*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / mortality
  • Stomach Neoplasms / pathology
  • Superoxide Dismutase / metabolism
  • Tumor Burden

Substances

  • Histones
  • Intracellular Signaling Peptides and Proteins
  • RNA, Long Noncoding
  • WDR5 protein, human
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Histone-Lysine N-Methyltransferase
  • Histone Acetyltransferases
  • KAT2A protein, human