Transcriptional control of the tumor- and hypoxia-marker carbonic anhydrase 9: A one transcription factor (HIF-1) show?

Biochim Biophys Acta. 2009 Apr;1795(2):162-72. doi: 10.1016/j.bbcan.2009.01.001. Epub 2009 Jan 22.


Transcriptional activation by hypoxia is mediated by the hypoxia-inducible factor (HIF) via binding to the hypoxia-responsive element (HRE). Hypoxia in solid tumors associates with poorer outcome of the disease and reliable cellular markers of tumor hypoxia would represent a valuable diagnostic marker and a potential therapeutic target. In this category, carbonic anhydrase IX (CAIX) is one of the most promising candidates. Here, we summarize the knowledge about transcriptional regulation of CA9. The HRE is the central regulatory element in the CA9 promoter, whereas other elements are limited to lesser roles of amplification of signals received at the HRE. The analysis of known mechanisms of activation of CA9 reveals the prominent role of the HIF-1 pathway. Experimental paradigms with uncoupled HIF-1alpha stability and transcriptional activity (pericellular hypoxia, proteasomal inhibitor) provide evidence that CA9 expression monitors transcriptional activity of HIF-1, rather than the abundance of HIF-1alpha. Furthermore, these paradigms could provide a corollary to some of the apparently discordant cases (CAIX+, HIF-1alpha-) or (CAIX-, HIF-1alpha+) observed in vivo. In conclusion, the existing data support the notion that CA9, due to the unique structure of its promoter, is one of the most sensitive endogenous sensors of HIF-1 activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Antigens, Neoplasm / genetics*
  • Base Sequence
  • Biomarkers
  • Biomarkers, Tumor
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases / genetics*
  • Cell Hypoxia*
  • Epigenesis, Genetic
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Hypoxia-Inducible Factor 1 / physiology*
  • Molecular Sequence Data
  • Neoplasms / enzymology*
  • Neoplasms / etiology
  • Promoter Regions, Genetic
  • Response Elements / physiology
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / physiology


  • Antigens, Neoplasm
  • Biomarkers
  • Biomarkers, Tumor
  • Hypoxia-Inducible Factor 1
  • Tumor Suppressor Protein p53
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases