Hypoxia induced expression of histone lysine demethylases: implications in oxygen-dependent retinal neovascular diseases.

Abstract

Hypoxia inducible factor (HIF) plays a critical role in cellular adaptation to hypoxia by regulating the expression of essential genes. Pathological activation of this pathway leads to the expression of pro-angiogenic factors during the neovascularization in cancer and retinal diseases. Little is known about the epigenetic regulations during HIF-mediated transcription and activation of pro-angiogenic genes in oxygen-dependent retinal diseases. Here, we show that hypoxia induces the expression of a number of histone lysine demethylases (KDMs) in retinal pigment epithelial cells. Moreover, we show that the expression of pro-angiogenic genes (ADM, GDF15, HMOX1, SERPE1 and SERPB8) is dependent on KDMs under hypoxic conditions. Further, treating the cells with a general KDM inhibitor blocks the expression of these pro-angiogenic genes. Results from these studies identify a new layer of epigenetic transcription regulation under hypoxic conditions and suggest that specific inhibitors of KDMs such as JMJD1A can be a new therapeutic approach to treat diseases caused by the hypoxia induced neovascularization in cancer and retinal diseases.

• Authors: V K Chaithanya Ponnaluri, Ramya Krishna Vadlapatla, Divya Teja Vavilala, Dhananjay Pal, Ashim K Mitra, Mridul Mukherji
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 415 Issue 2 Pg. 373-7 (Nov 18 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 22037463 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• ADM protein, human
• Amino Acids, Dicarboxylic
• GDF15 protein, human
• Growth Differentiation Factor 15
• Adrenomedullin
• Histone Demethylases
• HMOX1 protein, human
• Heme Oxygenase-1
• Oxygen
• oxalylglycine

Topics

• Adrenomedullin (genetics)
• Amino Acids, Dicarboxylic (pharmacology)
• Cell Hypoxia (genetics)
• Cell Line, Tumor
• Epigenesis, Genetic
• Growth Differentiation Factor 15 (genetics)
• Heme Oxygenase-1 (genetics)
• Histone Demethylases (biosynthesis, genetics)
• Humans
• Oxygen (metabolism)
• Retinal Neovascularization (enzymology, genetics)
• Retinal Pigment Epithelium (drug effects, enzymology)