Hypoxia-inducible factor 1α mediates the down-regulation of superoxide dismutase 2 in von Hippel-Lindau deficient renal clear cell carcinoma

Biochem Biophys Res Commun. 2013 May 24;435(1):46-51. doi: 10.1016/j.bbrc.2013.04.034. Epub 2013 Apr 20.

Abstract

Hypoxia-inducible factor 1α (HIF-1α) is an oxygen-sensitive subunit of HIF-1, the master transcription factor for cellular response to hypoxia. Down-regulation of the mitochondrial enzyme superoxide dismutase 2 (SOD2) contributes to the stabilization of HIF-1α under hypoxia due to the decreased dismutation of superoxide radical. Here we report that HIF-1α could also regulate the expression of SOD2. We found that both stabilization of HIF-1α expression under nomoxia caused by pVHL deficiency and hypoxia treatment significantly reduced SOD2 expression, and shRNAs specifically against HIF-1α restored SOD2 expression in both circumstances. Further analyses with luciferase reporter assay and chromatin immunoprecipitation assay revealed that HIF-1α inhibited and directly bound to the hypoxia-responsive element in SOD2 promoter. These findings indicated the existence of a positive feedback between HIF-1α and SOD2 and provided new clues for understanding the molecular mechanisms of hypoxia adaptation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Blotting, Western
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Cell Hypoxia
  • Cell Line, Tumor
  • Down-Regulation*
  • Electrophoresis, Gel, Two-Dimensional
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunohistochemistry
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • RNA Interference
  • Response Elements / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human