HINT2 downregulation promotes colorectal carcinoma migration and metastasis

Oncotarget. 2017 Feb 21;8(8):13521-13531. doi: 10.18632/oncotarget.14587.

Abstract

Histidine triad nucleotide-binding 2 (HINT2), a member of the histidine triad proteins family, sensitizes cells to apoptosis in hepatocellular carcinoma. Here, we showed that HINT2 expression is lower in primary colorectal cancer (CRC) and metastasis tissues than in normal colorectal tissues, and that HINT2 abundance is inversely correlated with CRC tumor stage. Treating CRC cells with 5-aza-2'-deoxycytidine, a demethylating agent, upregulated HINT2, suggesting HINT2 downregulation is caused by methylation of the gene promoter. HINT2 downregulation increased tumor migration and invasion in vitro, promoted CRC cell metastasis in vivo, and increased expression of epithelial-to-mesenchymal transition (EMT) markers. Furthermore, HINT2 downregulation depended on hypoxia inducible factor (HIF)-2α-mediated transcriptional activation of zinc finger E-box-binding homeobox 1 (ZEB1). These results suggest that HINT2 downregulation promotes HIF-2α expression, which induces EMT and enhances CRC cell migration and invasion. HINT2 may thus a useful clinical indicator of CRC progression and metastasis risk.

Keywords: HIF-2α; HINT2; ZEB1; colorectal cancer; epithelial–mesenchymal transition.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Movement / physiology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Down-Regulation
  • Epithelial-Mesenchymal Transition
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Neoplasm Metastasis
  • Signal Transduction
  • Transfection
  • Zinc Finger E-box-Binding Homeobox 1 / genetics
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hint2 protein, human
  • Mitochondrial Proteins
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • endothelial PAS domain-containing protein 1