Paradoxical regulation of hypoxia inducible factor-1α (HIF-1α) by histone deacetylase inhibitor in diffuse large B-cell lymphoma.

Abstract

Hypoxia inducible factor (HIF) is important in cancer, as it regulates various oncogenic genes as well as genes involved in cell survival, proliferation, and migration. Elevated HIF-1 protein promotes a more aggressive tumor phenotype, and greater HIF-1 expression has been demonstrated to correlate with poorer prognosis, increased risk of metastasis and increased mortality. Recent reports suggest that HIF-1 activates autophagy, a lysosomal degradation pathway which may promote tumor cell survival. We show here that HIF-1α expression is constitutively active in multiple diffuse large B cell lymphoma (DLBCL) cell lines under normoxia and it is regulated by the PI3K/AKT pathway. PCI-24781, a pan histone deacetylase inhibitor (HDACI), enhanced accumulation of HIF-1α and induced autophagy initially, while extended incubation with the drug resulted in inhibition of HIF-1α. We tested the hypothesis that PCI-24781- induced autophagy is mediated by HIF-1α and that inhibition of HIF-1α in these cells results in attenuation of autophagy and decreased survival. We also provide evidence that autophagy serves as a survival pathway in DLBCL cells treated with PCI-24781 which suggests that the use of autophagy inhibitors such as chloroquine or 3-methyl adenine in combination with PCI-24781 may enhance apoptosis in lymphoma cells.

• Authors: Savita Bhalla, Andrew M Evens, Sheila Prachand, Paul T Schumacker, Leo I Gordon
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e81333 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24312289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzofurans
• HIF1A protein, human
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Hypoxia-Inducible Factor 1, alpha Subunit
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• AMP-Activated Protein Kinases
• abexinostat

Topics

• AMP-Activated Protein Kinases (metabolism)
• Autophagy (drug effects)
• Benzofurans (pharmacology)
• Cell Survival (drug effects)
• Drug Synergism
• Enzyme Activation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Lymphoma, Large B-Cell, Diffuse (pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)