FHL family members suppress vascular endothelial growth factor expression through blockade of dimerization of HIF1α and HIF1β

Four and a half LIM domain (FHL) proteins belong to a family of LIM-only proteins that have been implicated in the development and progression of various types of cancers. However, the role of FHL proteins in tumor angiogenesis remains to be elucidated. Herein, we demonstrate that FHL1-3 decrease the promoter activity and expression of vascular endothelial growth factor (VEGF), the key regulator of angiogenesis in cancer growth and progression as well as an important target gene of the transcription factor hypoxia-inducible factor 1 (HIF1a/HIF1 beta). FHL1-3 interacted with HIF1a both in vitro and in vivo. A single LIM domain of FHL1 was sufficient for its interaction with HIF1a. FHL1 interacted with the HIF1a region containing basic helix-loop-helix (bHLH) motif and PER-ARNT-SIM domain, both of which aid in dimerization with HIF1 beta and DNA binding. FHL1-3 inhibited HIF1 transcriptional activity and HIF1-mediated VEGF expression in a hypoxia-independent manner. Moreover, FHL1 blocked HIF1a-HIF1 beta heterodimerization and HIF1a recruitment to the VEGF promoter. These data suggest that FHL proteins are involved in negative regulation of VEGF possibly by interfering with the dimerization and DNA binding of HIF1 subunits and may play an important role in tumor angiogenesis. (c) 2012 IUBMB. IUBMB Life, 64(11): 921930, 2012