Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge

Cancer Sci. 2018 Mar;109(3):560-571. doi: 10.1111/cas.13483. Epub 2018 Jan 27.


Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF-1 activity have been implicated in the pathogenesis of various diseases including malignant tumors and, thus, elucidating the molecular mechanisms underlying the activation of HIF-1 is eagerly desired for the development of novel anti-cancer strategies. The importance of oxygen-dependent and ubiquitin-mediated proteolysis of the regulatory subunit of HIF-1 (HIF-1α) was first reported in 1997. Since then, accumulating evidence has shown that HIF-1α may become stable and active even under normoxic conditions; for example, when disease-associated genetic and functional alterations in some genes trigger the aberrant activation of HIF-1 regardless of oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF-1 activity from conventional oxygen- and proteolysis-dependent mechanisms to up-to-the-minute information on cancer-associated genetic and functional alteration-mediated mechanisms.

Keywords: gene expression; hypoxia-inducible factor 1 (HIF-1); molecular mechanism; tumor hypoxia.

Publication types

  • Review

MeSH terms

  • Cell Hypoxia
  • Dioxygenases / metabolism
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Humans
  • Hypoxia-Inducible Factor 1 / genetics*
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Ubiquitination


  • Hypoxia-Inducible Factor 1
  • Dioxygenases