Hypoxia induced expression of histone lysine demethylases: implications in oxygen-dependent retinal neovascular diseases.
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.
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO 64108-2718, USA.
V K Chaithanya
VK
Ponnaluri
Ramya Krishna
RK
Vadlapatla
Divya Teja
DT
Vavilala
Dhananjay
D
Pal
Ashim K
AK
Mitra
Mridul
M
Mukherji
D053607:Adrenomedullin / Q000235:genetics; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D055436:Growth Differentiation Factor 15 / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics; D056466:Histone Demethylases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D010100:Oxygen / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000201:enzymology* / Q000235:genetics*; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000201:enzymology*
C507862:ADM protein, human; D000600:Amino Acids, Dicarboxylic; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D053607:Adrenomedullin; D056466:Histone Demethylases; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D010100:Oxygen; C040947:oxalylglycine