Epigenetic regulation of soluble guanylate cyclase (sGC) ß1 in breast cancer cells.

Soluble guanylate cyclase (sGC) is a heterodimer composed of α and ß subunits. The loss of sGCß1 has been implicated in several vascular and nonvascular diseases. Our analysis showed that higher levels of sGCß1 in breast cancer tissues are correlated with greater survival probability than lower sGCß1 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 -ß1 expression in human breast cancer MDA-MB-231 and MDA-MB-468 cell lines. The class I HDAC inhibitors increased the expression of sGCß1 more than sGCα1. Transient overexpression of HDAC3, but not HDAC1 or HDAC2, significantly reduced sGCß1 mRNA. Chromatin immunoprecipitation assay confirmed an enhanced binding of HDAC3 to the sGCß1 proximal promoter, which could be reversed by panobinostat (LBH-589) treatment. Mutations at the CCAAT binding sequence, a major element regulating sGCß1 expression, markedly reduced the efficacy of LBH-589 in augmenting sGCß1 promoter activity. LBH-589 markedly enhanced the binding of nuclear transcription factor Y, subunit α, to the sGCß1 promoter (CCAAT binding sequence). In summary, HDAC3 is an endogenous antagonist of sGCß1 expression. Inhibition of HDAC3 with targeted therapy could benefit treatment of the diseases associated with sGCß1 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) ß1 in breast cancer cells.

NOS-2 signaling and cancer therapy.

The role of NO and cGMP signaling in tumor biology has been extensively studied during the past three decades. However, whether the pathway is beneficial or detrimental in cancer is still open to question. We suggest several reasons for this ambiguity: first, although NO participates in normal signaling (e.g., vasodilation and neurotransmission), NO is also a cytotoxic or apoptotic molecule when produced at high concentrations by inducible nitric-oxide synthase (iNOS or NOS-2). In addition, the cGMP-dependent (NO/sGC/cGMP pathway) and cGMP-independent (NO oxidative pathway) components may vary among different tissues and cell types. Furthermore, solid tumors contain two compartments: the parenchyma (neoplastic cells) and the stroma (nonmalignant supporting tissues including connective tissue, blood vessels, and inflammatory cells) with different NO biology. Thus, the NO/sGC/cGMP signaling molecules in tumors as well as the surrounding tissue must be further characterized before targeting this signaling pathway for tumor therapy. In this review, we focus on the NOS-2 expression in tumor and surrounding cells and summarized research outcome in terms of cancer therapy. We propose that a normal function of the sGC-cGMP signaling axis may be important for the prevention and/or treatment of malignant tumors. Inhibiting NOS-2 overexpression and the tumor inflammatory microenvironment, combined with normalization of the sGC/cGMP signaling may be a favorable alternative to chemotherapy and radiotherapy for malignant tumors.