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Regulation of the HIF-1alpha stability by histone deacetylases

Se-Hee Kim1, Joo-Won Jeong, Jeong Ae Park

  • 1NeuroVascular Coordination Research Center, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.

Oncology Reports
|February 3, 2007
PubMed

Insights

Histone deacetylase inhibitors decrease hypoxia-inducible factor 1-alpha (HIF-1alpha) levels. Class I HDACs, specifically HDAC1 and 3, stabilize HIF-1alpha by direct binding, impacting tumor angiogenesis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Histone deacetylase inhibitors (HDACIs) show anti-angiogenic effects, but their mechanism is not fully understood.
  • Tumor angiogenesis is crucial for cancer growth and is regulated by hypoxia-inducible factor 1 (HIF-1).

Purpose of the Study:

  • To elucidate the mechanism by which HDACIs affect HIF-1alpha protein levels and activity.
  • To investigate the role of specific HDACs in regulating HIF-1alpha stability and function.

Main Methods:

  • Treatment of human and mouse tumor cell lines with various HDACIs (TSA, SB, Apicidin, VPA).
  • Assessment of HIF-1alpha protein levels and HIF-1 transcriptional activity.
  • Immunoprecipitation and in vitro binding assays to determine direct interactions between HDACs and HIF-1alpha.

Main Results:

  • HDACIs significantly reduced HIF-1alpha protein levels and HIF-1 transcriptional activity.
  • Class I HDACs, HDAC1 and HDAC3, were found to enhance HIF-1alpha stability and HIF-1 transactivation under hypoxic conditions.
  • HDAC1 and HDAC3 directly bind to the oxygen-dependent degradation domain of HIF-1alpha.

Conclusions:

  • HDAC1 and HDAC3 act as positive regulators of HIF-1alpha stability through direct interaction.
  • These findings suggest a novel mechanism involving HDAC1/3 and HIF-1alpha in regulating HIF-1-induced tumor angiogenesis.

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