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

• Published in: Biochemical and biophysical research communications 2011-11, Vol.415 (2), p.373-377
• Main Authors: Ponnaluri, V.K. Chaithanya, Vadlapatla, Ramya Krishna, Vavilala, Divya Teja, Pal, Dhananjay, Mitra, Ashim K., Mukherji, Mridul
• Format: Article
• Language: English
• Subjects: Adaptations; Adrenomedullin - genetics; Amino Acids, Dicarboxylic - pharmacology; Angiogenesis; Cell Hypoxia - genetics; Cell Line, Tumor; Demethylase; Epigenesis, Genetic; Epigenetics; Growth Differentiation Factor 15 - genetics; Heme Oxygenase-1 - genetics; Histone Demethylases - biosynthesis; Histone Demethylases - genetics; Humans; Hypoxia signaling; Jumonji domain; Oxygen - metabolism; Retinal Neovascularization - enzymology; Retinal Neovascularization - genetics; Retinal Pigment Epithelium - drug effects; Retinal Pigment Epithelium - enzymology; Transcription regulation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2011.10.075

[Display omitted] ► HIF pathway plays vital role in neovascularization in cancer and retinal diseases. ► Hypoxia induces expression of histone lysine demethylases (KDMs) in a retinal cell. ► The expression of pro-angiogenic genes is dependent on KDMs under hypoxic conditions. ► Treating cells with a KDM inhibitor blocks the expression of pro-angiogenic genes. ► Specific inhibitors of KDMs can be used to treat hypoxia induced neovascularization. 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.