HOXD-AS1 confers cisplatin resistance in gastric cancer through epigenetically silencing PDCD4 via recruiting EZH2

Open Biol. 2019 Sep 27;9(9):190068. doi: 10.1098/rsob.190068. Epub 2019 Sep 25.

Abstract

Increasing evidence suggests that dysregulation of long non-coding RNAs (lncRNAs) is implicated in chemoresistance in cancers. However, the function and molecular mechanisms of lncRNAs in gastric cancer chemoresistance are still not well understood. In this study, we aimed to investigate the functional role and the underlying molecular mechanisms of lncRNA HOXD cluster antisense RNA 1 (HOXD-AS1) in cisplatin (DDP) resistance in gastric cancer. Our results revealed that HOXD-AS1 was upregulated in DDP-resistant gastric cancer tissues and cells. Patients with gastric cancer with high HOXD-AS1 expression levels had a poor prognosis. Knockdown of HOXD-AS1 facilitated the sensitivity of DDP-resistant gastric cancer cells to DDP. Additionally, HOXD-AS1 epigenetically silenced PDCD4 through binding to the histone methyltransferase enhancer of zeste homologue 2 (EZH2) on the promoter of PDCD4, thus increasing H3K27me3. More importantly, PDCD4 silencing counteracted HOXD-AS1 knockdown-mediated enhancement of DDP sensitivity in DDP-resistant gastric cancer cells. In summary, HOXD-AS1 led to DDP resistance in gastric cancer by epigenetically suppressing PDCD4 expression, providing a novel therapeutic strategy for patients with gastric cancer with chemoresistance.

Keywords: EZH2; PDCD4; cisplatin; gastric cancer; lncRNA HOXD-AS1.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Cisplatin / pharmacology
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Gene Silencing*
  • Humans
  • Mice
  • Models, Biological
  • Protein Binding
  • RNA, Long Noncoding / genetics*
  • RNA-Binding Proteins / genetics*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Apoptosis Regulatory Proteins
  • PDCD4 protein, human
  • RNA, Long Noncoding
  • RNA-Binding Proteins
  • long non-coding RNA HOXD-AS1, human
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Cisplatin