Histone Deacetylase 7 Controls Endothelial Cell Growth Through Modulation of {beta}-Catenin
A Margariti,
A Zampetaki,
Q Xiao,
B Zhou,
E Karamariti,
D Martin,
X Yin,
M Mayr,
H Li,
Z Zhang,
E De Falco,
Y Hu,
G Cockerill,
Q Xu
and
L. Zeng
Abstract
Rationale: Histone deacetylase (HDAC)7 is expressed in the early stages of embryonic development and may play a role in endothelial function.
Objective: This study aimed to investigate the role of HDAC7 in endothelial cell (EC) proliferation and growth and the underlying mechanism.
Methods and Results: Overexpression of HDAC7 by adenoviral gene transfer suppressed human umbilical vein endothelial cell (HUVEC) proliferation by preventing nuclear translocation of β-catenin and downregulation of T-cell factor-1/Id2 (inhibitor of DNA binding 2) and cyclin D1, leading to G1 phase elongation. Further assays with the TOPFLASH reporter and quantitative RT-PCR for other β-catenin target genes such as Axin2 confirmed that overexpression of HDAC7 decreased β-catenin activity. Knockdown of HDAC7 by lentiviral short hairpin RNA transfer induced β-catenin nuclear translocation but downregulated cyclin D1, cyclin E1 and E2F2, causing HUVEC hypertrophy. Immunoprecipitation assay and mass spectrometry analysis revealed that HDAC7 directly binds to β-catenin and forms a complex with 14-3-3 , , and proteins. Vascular endothelial growth factor treatment induced HDAC7 degradation via PLC-IP3K (phospholipase C–inositol-1,4,5-trisphosphate kinase) signal pathway and partially rescued HDAC7-mediated suppression of proliferation. Moreover, vascular endothelial growth factor stimulation suppressed the binding of HDAC7 with β-catenin, disrupting the complex and releasing β-catenin to translocate into the nucleus.
Conclusions: These findings demonstrate that HDAC7 interacts with β-catenin keeping ECs in a low proliferation stage and provides a novel insight into the mechanism of HDAC7-mediated signal pathways leading to endothelial growth.
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