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

Abstract

SummaryFour 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/ HIF1b). 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 HIF1b and DNA binding. FHL1-3 inhibited HIF1 transcriptional activity and HIF1-mediated VEGF expression in a hypoxia-independent manner. Moreover, FHL1 blocked HIF1a-HIF1b 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. Keywords four and a half LIM domain; vascular endothelial growth factor; hypoxia-inducible factor 1; protein-protein interaction; transcriptional activity.

The transcription factor GATA1 and the histone methyltransferase SET7 interact to promote VEGF-mediated angiogenesis and tumor growth and predict clinical outcome of breast cancer

“…Moreover, reciprocal coimmunoprecipitation experiments showed that GATA1, SET7, Pol II, and TFIIB interacted with each other (Figure 4H ). GATA1 did not interact with HIF1α although HIF1α interacted with four and a half LIM protein 1 (FHL1) as we previously reported [ 49 ] ( Supplementary Figure S7C ). Taken together, these results suggest that GATA1, SET7, Pol II, and TFIIB may form a preinitiation complex on the GATC site of VEGF promoter.…”

Chronic Ethanol Consumption Modulates Growth Factor Release, Mucosal Cytokine Production, and MicroRNA Expression in Nonhuman Primates

“…Since STAT3 and ARNT modulate HGF, VEGF and G-CSF expression a (Albasanz-Puig et al, 2012, Lin et al, 2012, Tacchini et al, 2003, Nguyen-Khac et al, 2006, Zhang et al, 2012, Zimmers et al, 2003), we analyzed HGF and VEGF levels by western blot in lysates of PBMC transfected with miRNA 181/221 and mimics or antagomirs and then stimulated with PMA/ionomycin (Fig 7D–F). Secretion of G-CSF into culture supernatant was carried using singleplex assay because we were not able to detect protein expression using the commercially available antibody (Fig 7G).…”

“…As STAT3 and ARNT modulate HGF, VEGF, and G-CSF expression (Albasanz-Puig et al, 2012;Lin et al, 2012; -Khac et al, 2006;Tacchini et al, 2003;Zhang et al, 2012;Zimmers et al, 2003), we analyzed HGF and VEGF levels by Western blot in lysates of PBMC transfected with miRNA 181/221 and mimics or antagomirs and then stimulated with PMA/ionomycin ( Fig. 7D-F).…”

Effects of FHL1 and P21 on hypoxia‑induced pulmonary vascular remodeling in neonatal rats

“…Nadeau et al ( 27 ) observed that vascular endothelial growth factor (VEGF) was upregulated in a neonatal pig model of HPH. In human HepG2 hepatoma cells, FHL1 decreased the expression and activity of VEGF by blocking the dimerization of HIF-1α and HIF-1β ( 28 ). Thus, FHL1 may have exerted similar effect in the current HPH neonatal rat model.…”