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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.
AuthorsSu Young Oh, Ji Yoon Seok, Young Sun Choi, Sung Hee Lee, Jong-Sup Bae, You Mie Lee
JournalMolecules and cells (Mol Cells) Vol. 38 Issue 6 Pg. 528-34 (Jun 2015) ISSN: 0219-1032 [Electronic] Korea (South)
PMID26013382 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Azepines
  • BIX 01294
  • Enzyme Inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Quinazolines
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase
Topics
  • Animals
  • Azepines (pharmacology)
  • Carcinoma, Hepatocellular (blood supply, drug therapy)
  • Chick Embryo
  • Enzyme Inhibitors (pharmacology)
  • Hep G2 Cells
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase (antagonists & inhibitors, metabolism)
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
  • Liver Neoplasms (blood supply, drug therapy)
  • Mice
  • Neovascularization, Pathologic (drug therapy, metabolism)
  • Quinazolines (pharmacology)
  • Signal Transduction

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