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 a...