Epigenetic regulation of soluble guanylate cyclase (sGC) β1 in breast cancer cells.
Soluble guanylate cyclase (sGC) is a heterodimer composed of α and β subunits. The loss of sGCβ1 has been implicated in several vascular and nonvascular diseases. Our analysis showed that higher levels of sGCβ1 in breast cancer tissues are correlated with greater survival probability than lower sGCβ1 levels. However, there is no information on sGC regulation by epigenetic mechanisms. We examined the role of histone deacetylase (HDAC) inhibitors in regulating sGCα1 and -β1 expression in human breast cancer MDA-MB-231 and MDA-MB-468 cell lines. The class I HDAC inhibitors increased the expression of sGCβ1 more than sGCα1. Transient overexpression of HDAC3, but not HDAC1 or HDAC2, significantly reduced sGCβ1 mRNA. Chromatin immunoprecipitation assay confirmed an enhanced binding of HDAC3 to the sGCβ1 proximal promoter, which could be reversed by panobinostat (LBH-589) treatment. Mutations at the CCAAT binding sequence, a major element regulating sGCβ1 expression, markedly reduced the efficacy of LBH-589 in augmenting sGCβ1 promoter activity. LBH-589 markedly enhanced the binding of nuclear transcription factor Y, subunit α, to the sGCβ1 promoter (CCAAT binding sequence). In summary, HDAC3 is an endogenous antagonist of sGCβ1 expression. Inhibition of HDAC3 with targeted therapy could benefit treatment of the diseases associated with sGCβ1 down-regulation and/or deficiency such as cancer and several vascular-related diseases.-Sotolongo, A., Mónica, F. Z., Kots, A., Xiao, H., Liu, J., Seto, E., Bian, K., Murad, F. Epigenetic regulation of soluble guanylate cyclase (sGC) β1 in breast cancer cells.
Department of Biochemistry and Molecular Medicine, George Washington University, Washington, District of Columbia, USA;
Alex
A
Sotolongo
Department of Biochemistry and Molecular Medicine, George Washington University, Washington, District of Columbia, USA; Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Sao Paulo, Brazil; and.
Fabiola Zakia
FZ
Mónica
Department of Biochemistry and Molecular Medicine, George Washington University, Washington, District of Columbia, USA;
Alex
A
Kots
Department of Biochemistry and Molecular Medicine, George Washington University, Washington, District of Columbia, USA;
Haijie
H
Xiao
Department of Biochemistry and Molecular Medicine, George Washington University, Washington, District of Columbia, USA;
Jun
J
Liu
Department of Biochemistry and Molecular Medicine, George Washington University, Washington, District of Columbia, USA; Cancer Center, George Washington University, Washington, District of Columbia, USA.
Edward
E
Seto
Department of Biochemistry and Molecular Medicine, George Washington University, Washington, District of Columbia, USA; bcmkxb@gwu.edu.
Ka
K
Bian
Department of Biochemistry and Molecular Medicine, George Washington University, Washington, District of Columbia, USA;
Ferid
F
Murad
D000107:Acetylation; D001943:Breast Neoplasms / Q000378:metabolism*; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005910:Glioma; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic; D000071756:Soluble Guanylyl Cyclase / Q000235:genetics / Q000378:metabolism*; D000099186:Histone Deacetylase 3
D023081:CCAAT-Binding Factor; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D000071756:Soluble Guanylyl Cyclase; D000099186:Histone Deacetylase 3
histone acetyltransferase; histone deacetylase; inhibitors