Histone deacetylase 7 controls endothelial cell growth through modulation of beta-catenin.
BACKGROUND
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.


RESULTS
Overexpression of HDAC7 by adenoviral gene transfer suppressed human umbilical vein endothelial cell (HUVEC) proliferation by preventing nuclear translocation of beta-catenin and downregulation of T-cell factor-1/Id2 (inhibitor of DNA binding 2) and cyclin D1, leading to G(1) phase elongation. Further assays with the TOPFLASH reporter and quantitative RT-PCR for other beta-catenin target genes such as Axin2 confirmed that overexpression of HDAC7 decreased beta-catenin activity. Knockdown of HDAC7 by lentiviral short hairpin RNA transfer induced beta-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 beta-catenin and forms a complex with 14-3-3 epsilon, zeta, and eta proteins. Vascular endothelial growth factor treatment induced HDAC7 degradation via PLCgamma-IP3K (phospholipase Cgamma-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 beta-catenin, disrupting the complex and releasing beta-catenin to translocate into the nucleus.


CONCLUSIONS
These findings demonstrate that HDAC7 interacts with beta-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.
Margariti
Andriana
A
Cardiovascular Division, King's College London British Heart Foundation Centre, London, United Kingdom.
Zampetaki
Anna
A
Xiao
Qingzhong
Q
Zhou
Boda
B
Karamariti
Eirini
E
Martin
Daniel
D
Yin
Xiaoke
X
Mayr
Manuel
M
Li
Hongling
H
Zhang
Zhongyi
Z
De Falco
Elena
E
Hu
Yanhua
Y
Cockerill
Gillian
G
Xu
Qingbo
Q
Zeng
Lingfang
L
D048948:14-3-3 Proteins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000256:Adenoviridae / Q000235:genetics; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D050703:E2F2 Transcription Factor / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D005822:Genetic Vectors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy; D047468:Immunoprecipitation; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism; D013058:Mass Spectrometry; D018919:Neovascularization, Physiologic; D015513:Oncogene Proteins / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D048948:14-3-3 Proteins; C530104:CCND1 protein, human; C475820:CCNE1 protein, human; C495270:CTNNB1 protein, human; D019927:Cyclin E; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D015513:Oncogene Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C482983:YWHAE protein, human; C482984:YWHAH protein, human; D051176:beta Catenin; D019938:Cyclin D1; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase; D051966:Phospholipase C gamma; C543273:HDAC7 protein, human; D006655:Histone Deacetylases