HDAC6 Enhances Endoglin Expression Through Deacetylation of Transcription Factor SP1, Potentiating BMP9-Induced Angiogenesis

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2024 Mar 27

PMID 38534334

Authors

Chen Sun

Kuifang Xie

Lejie Yang

Shengyang Cai

Mingjie Wang

Yizhun Zhu

Beibei Tao

Yichun Zhu

Affiliations

Soon will be listed here.

Abstract

Histone deacetylase 6 (HDAC6) plays a crucial role in the acetylation of non-histone proteins and is notably implicated in angiogenesis, though its underlying mechanisms were previously not fully understood. This study conducted transcriptomic and proteomic analyses on vascular endothelial cells with HDAC6 knockdown, identifying endoglin (ENG) as a key downstream protein regulated by HDAC6. This protein is vital for maintaining vascular integrity and plays a complex role in angiogenesis, particularly in its interaction with bone morphogenetic protein 9 (BMP9). In experiments using human umbilical vein endothelial cells (HUVECs), the pro-angiogenic effects of BMP9 were observed, which diminished following the knockdown of HDAC6 and ENG. Western blot analysis revealed that BMP9 treatment increased SMAD1/5/9 phosphorylation, a process hindered by HDAC6 knockdown, correlating with reduced ENG expression. Mechanistically, our study indicates that HDAC6 modulates ENG transcription by influencing promoter activity, leading to increased acetylation of transcription factor SP1 and consequently altering its transcriptional activity. Additionally, the study delves into the structural role of HDAC6, particularly its CD2 domain, in regulating SP1 acetylation and subsequently ENG expression. In conclusion, the present study underscores the critical function of HDAC6 in modulating SP1 acetylation and ENG expression, thereby significantly affecting BMP9-mediated angiogenesis. This finding highlights the potential of HDAC6 as a therapeutic target in angiogenesis-related processes.

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References

Saito T, Bokhove M, Croci R, Zamora-Caballero S, Han L, Letarte M . Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1. Cell Rep. 2017; 19(9):1917-1928. PMC: 5464963. DOI: 10.1016/j.celrep.2017.05.011. View

Hai Y, Christianson D . Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat Chem Biol. 2016; 12(9):741-7. PMC: 4990478. DOI: 10.1038/nchembio.2134. View

Shvedunova M, Akhtar A . Modulation of cellular processes by histone and non-histone protein acetylation. Nat Rev Mol Cell Biol. 2022; 23(5):329-349. DOI: 10.1038/s41580-021-00441-y. View

David L, Mallet C, Keramidas M, Lamande N, Gasc J, Dupuis-Girod S . Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ Res. 2008; 102(8):914-22. PMC: 2561062. DOI: 10.1161/CIRCRESAHA.107.165530. View

David L, Mallet C, Mazerbourg S, Feige J, Bailly S . Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood. 2006; 109(5):1953-61. DOI: 10.1182/blood-2006-07-034124. View

Jin G, Wang K, Zhao Y, Yuan S, He Z, Zhang J . Targeting histone deacetylases for heart diseases. Bioorg Chem. 2023; 138:106601. DOI: 10.1016/j.bioorg.2023.106601. View

Snellings D, Gallione C, Clark D, Vozoris N, Faughnan M, Marchuk D . Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1. Am J Hum Genet. 2019; 105(5):894-906. PMC: 6848992. DOI: 10.1016/j.ajhg.2019.09.010. View

Seidel C, Schnekenburger M, Dicato M, Diederich M . Histone deacetylase 6 in health and disease. Epigenomics. 2015; 7(1):103-18. DOI: 10.2217/epi.14.69. View

Botella L, Sanchez-Elsner T, Rius C, Corbi A, Bernabeu C . Identification of a critical Sp1 site within the endoglin promoter and its involvement in the transforming growth factor-beta stimulation. J Biol Chem. 2001; 276(37):34486-94. DOI: 10.1074/jbc.M011611200. View

10.

Plumitallo S, Ruiz-Llorente L, Langa C, Morini J, Babini G, Cappelletti D . Functional analysis of a novel ENG variant in a patient with hereditary hemorrhagic telangiectasia (HHT) identifies a new Sp1 binding-site. Gene. 2018; 647:85-92. DOI: 10.1016/j.gene.2018.01.007. View

11.

Boyault C, Zhang Y, Fritah S, Caron C, Gilquin B, Kwon S . HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev. 2007; 21(17):2172-81. PMC: 1950856. DOI: 10.1101/gad.436407. View

12.

Eming S, Martin P, Tomic-Canic M . Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014; 6(265):265sr6. PMC: 4973620. DOI: 10.1126/scitranslmed.3009337. View

13.

Suzuki Y, Ohga N, Morishita Y, Hida K, Miyazono K, Watabe T . BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo. J Cell Sci. 2010; 123(Pt 10):1684-92. DOI: 10.1242/jcs.061556. View

14.

Zhu Y, Feng M, Wang B, Zheng Y, Jiang D, Zhao L . New insights into the non-enzymatic function of HDAC6. Biomed Pharmacother. 2023; 161:114438. DOI: 10.1016/j.biopha.2023.114438. View

15.

Zhang D, Hu X, Henning R, Brundel B . Keeping up the balance: role of HDACs in cardiac proteostasis and therapeutic implications for atrial fibrillation. Cardiovasc Res. 2015; 109(4):519-26. DOI: 10.1093/cvr/cvv265. View

16.

Perez-Gutierrez L, Ferrara N . Biology and therapeutic targeting of vascular endothelial growth factor A. Nat Rev Mol Cell Biol. 2023; 24(11):816-834. DOI: 10.1038/s41580-023-00631-w. View

17.

Saito M, Hess D, Eglinger J, Fritsch A, Kreysing M, Weinert B . Acetylation of intrinsically disordered regions regulates phase separation. Nat Chem Biol. 2018; 15(1):51-61. DOI: 10.1038/s41589-018-0180-7. View

18.

Liu S, Wang Z, Zhu R, Wang F, Cheng Y, Liu Y . Three Differential Expression Analysis Methods for RNA Sequencing: limma, EdgeR, DESeq2. J Vis Exp. 2021; (175). DOI: 10.3791/62528. View

19.

Miyake Y, Keusch J, Wang L, Saito M, Hess D, Wang X . Structural insights into HDAC6 tubulin deacetylation and its selective inhibition. Nat Chem Biol. 2016; 12(9):748-54. DOI: 10.1038/nchembio.2140. View

20.

Richter A, Alexdottir M, Magnus S, Richter T, Morikawa M, Zwijsen A . EGFL7 Mediates BMP9-Induced Sprouting Angiogenesis of Endothelial Cells Derived from Human Embryonic Stem Cells. Stem Cell Reports. 2019; 12(6):1250-1259. PMC: 6565989. DOI: 10.1016/j.stemcr.2019.04.022. View