title: The Histone Methyltransferase Inhibitor BIX01294 Inhibits HIF-1α Stability and Angiogenesis.
abstract: Hypoxia-inducible factor (HIF) is a key regulator of tumor growth and angiogenesis. Recent studies have shown that, BIX01294, a G9a histone methyltransferase (HMT)-specific inhibitor, induces apoptosis and inhibits the proliferation, migration, and invasion of cancer cells. However, not many studies have investigated whether inhibition of G9a HMT can modulate HIF-1α stability and angiogenesis. Here, we show that BIX01294 dose-dependently decreases levels of HIF-1α in HepG2 human hepatocellular carcinoma cells. The half-life of HIF-1α, expression of proline hydroxylase 2 (PHD2), hydroxylated HIF-1α and von Hippel-Lindau protein (pVHL) under hypoxic conditions were decreased by BIX01294. The mRNA expression and secretion of vascular endothelial growth factor (VEGF) were also significantly reduced by BIX01294 under hypoxic conditions in HepG2 cells. BIX01294 remarkably decreased angiogenic activity induced by VEGF in vitro, ex vivo, and in vivo, as demonstrated by assays using human umbilical vein endothelial cells (HUVECs), mouse aortic rings, and chick chorioallantoic membranes (CAMs), respectively. Furthermore, BIX01294 suppressed VEGF-induced matrix metalloproteinase 2 (MMP2) activity and inhibited VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR-2), focal adhesion kinase (FAK), and paxillin in HUVECs. In addition, BIX01294 inhibited VEGF-induced formation of actin cytoskeletal stress fibers. In conclusion, we demonstrated that BIX01294 inhibits HIF-1α stability and VEGF-induced angiogenesis through the VEGFR-2 signaling pathway and actin cytoskeletal remodeling, indicating a promising approach for developing novel therapeutics to stop tumor progression.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, National Basic Research Laboratory of Vascular Homeostasis Regulation, Daegu 702-701, Korea.
authors.forename: Su Young
authors.initials: SY
authors.lastname: Oh
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, National Basic Research Laboratory of Vascular Homeostasis Regulation, Daegu 702-701, Korea.
authors.forename: Ji Yoon
authors.initials: JY
authors.lastname: Seok
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, National Basic Research Laboratory of Vascular Homeostasis Regulation, Daegu 702-701, Korea.
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Choi
authors.affiliation: College of Nursing, Kyungpook National University, Daegu 702-701, Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, National Basic Research Laboratory of Vascular Homeostasis Regulation, Daegu 702-701, Korea.
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, National Basic Research Laboratory of Vascular Homeostasis Regulation, Daegu 702-701, Korea.
authors.forename: You Mie
authors.initials: YM
authors.lastname: Lee
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000188:drug therapy*; D002642:Chick Embryo; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056945:Hep G2 Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008113:Liver Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D001381:Azepines; C518299:BIX 01294; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011799:Quinazolines; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
keywords: BIX01294; G9a HMT inhibitor; HIF-1α; angiogenesis