A domain responsible for HIF-1alpha degradation by YC-1, a novel anticancer agent

Int J Oncol. 2006 Jul;29(1):255-60.


HIF-1alpha is believed to promote tumor growth and metastasis, and many efforts have been made to develop new anticancer agents based on HIF-1alpha inhibition. YC-1 is a widely used HIF-1alpha inhibitor both in vitro and in vivo, and is being developed as a novel class of anticancer drug. However, little is known about the mechanism by which YC-1 degrades HIF-1alpha. As the first step for understanding the mechanism of action of YC-1, we here identified the HIF-1alpha domain responsible for YC-1-induced protein degradation. YC-1 blocked the HIF-1alpha induction by hypoxia, iron chelation, and proteasomal inhibition and also degraded ectopically expressed HIF-1alpha. In deletion analyses, C-terminal HIF-1alpha was found to be sensitively degraded by YC-1. Using a GFP-fusion method, the YC-1-induced degradation domain was identified as the aa. 720-780 region of HIF-1alpha. We next tested the possible involvement of HDAC7 or OS-9 in YC-1-induced HIF-1alpha degradation. However, their binding to HIF-1alpha was not affected by YC-1, suggesting that they are not involved in the YC-1 action. It is also suggested that YC-1 targets a novel pathway regulating HIF-1alpha stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Hypoxia
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Gene Expression / drug effects*
  • Green Fluorescent Proteins / genetics
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / chemistry
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Indazoles / pharmacology*
  • Mutation
  • Protein Structure, Tertiary / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transfection


  • Antineoplastic Agents
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indazoles
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins
  • 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole