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The angiogenesis suppressor gene AKAP12 is under the epigenetic control of HDAC7 in endothelial cells

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A Correction to this article was published on 07 November 2023

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Abstract

Histone deacetylases (HDACs) are a family of 18 enzymes that deacetylate lysine residues of both histone and nonhistone proteins and to a large extent govern the process of angiogenesis. Previous studies have shown that specific inhibition of HDAC7 blocks angiogenesis both in vitro and in vivo. However, the underlying molecular mechanisms are not fully understood and hence preclude any meaningful development of suitable therapeutic modalities. The goal of the present study was to further the understanding of HDAC7 epigenetic control of angiogenesis in human endothelial cells using the proteomic approach. The underlying problem was approached through siRNA-mediated gene-expression silencing of HDAC7 in human umbilical vein endothelial cells (HUVECs). To this end, HUVEC proteins were extracted and proteomically analyzed. The emphasis was placed on up-regulated proteins, as these may represent potential direct epigenetic targets of HDAC7. Among several proteins, A-kinase anchor protein 12 (AKAP12) was the most reproducibly up-regulated protein following HDAC7 depletion. This overexpression of AKAP12 was responsible for the inhibition of migration and tube formation in HDAC7-depleted HUVEC. Mechanistically, H3 histones associated with AKAP12 promoter were acetylated following the removal of HDAC7, leading to an increase in its mRNA and protein levels. AKAP12 is responsible for protein kinase C mediated phosphorylation of signal transducer and activator of transcription 3 (STAT3). Phosphorylated STAT3 increasingly binds to the chromatin and AKAP12 promoter and is necessary for maintaining the elevated levels of AKAP12 following HDAC7 knockdown. We demonstrated for the first time that AKAP12 tumor/angiogenesis suppressor gene is an epigenetic target of HDAC7, whose elevated levels lead to a negative regulation of HUVEC migration and inhibit formation of tube-like structures.

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Abbreviations

HATs:

Histone acetyltransferases

HDACs:

Histone deacetylases

HDACIs:

HDAC inhibitors

HUVECs:

Human umbilical vein endothelial cells

siRNA:

Small interfering RNA

ECGS:

Endothelial cell growth supplement

ChIP:

Chromatin immunoprecipitation

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Acknowledgments

D. Mottet is a Research Associate and A. Bellahcène is a Senior Research Associate of the FNRS. N. Matheus is the FRIA Doctoral Fellow and B. Dumont is the Televie Doctoral Fellow of the FNRS. The authors acknowledge the GIGA-Proteomics Platform of the ULg and Diagenode, Liege, Belgium for experimental support. The authors are particularly thankful to Prof. Irwin Gelman, Roswell Park Cancer Institute, USA, for his helpful discussions. This work was supported by grants from the Walloon Region (NEO-ANGIO), the University of Liège (Centre Anti-Cancéreux) as well as by FRIA and TELEVIE grants from the National Fund for Scientific Research (FNRS), Belgium.

Conflict of interest

Authors have nothing to disclose and declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Metastasis Research Laboratory, GIGA-Cancer, University Hospital, University of Liège, Bat. B23, CHU Sart Tilman, 4000, Liège, Belgium

    Andrei Turtoi, Denis Mottet, Nicolas Matheus, Bruno Dumont, Paul Peixoto, Vincent Hennequière, Akeila Bellahcène & Vincent Castronovo

  2. Laboratory of Mass Spectrometry, University of Liège, Bat. B6C, 4000, Liège, Belgium

    Andrei Turtoi & Edwin De Pauw

  3. Laboratory of Connective Tissues Biology, GIGA-Cancer, University Hospital, University of Liège, Bat. B23, CHU Sart Tilman, 4000, Liège, Belgium

    Christophe Deroanne & Alain Colige

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  1. Andrei Turtoi
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  2. Denis Mottet
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Correspondence to Andrei Turtoi or Vincent Castronovo.

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Turtoi, A., Mottet, D., Matheus, N. et al. The angiogenesis suppressor gene AKAP12 is under the epigenetic control of HDAC7 in endothelial cells. Angiogenesis 15, 543–554 (2012). https://doi.org/10.1007/s10456-012-9279-8

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  • DOI: https://doi.org/10.1007/s10456-012-9279-8

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