Epigenetic regulation of soluble guanylate cyclase (sGC) 1 in breast cancer cells

Autor(es)

Sotolongo, Alex ; Monica, Fabiola Zakia ; Kots, Alex ; Xiao, Haijie ; Liu, Jun ; Seto, Edward ; Bian, Ka ; Murad, Ferid

• Tipo de documento: Artigo Científico
• Fonte: FASEB JOURNAL; v. 30, n. 9, p. 3171-3180, SEP 2016.
• Citações Web of Science: 4

Resumo

Soluble guanylate cyclase (sGC) is a heterodimer composed of and subunits. The loss of sGC1 has been implicated in several vascular and nonvascular diseases. Our analysis showed that higher levels of sGC1 in breast cancer tissues are correlated with greater survival probability than lower sGC1 levels. However, there is no information on sGC regulation by epigenetic mechanisms. We examined the role of histone deacetylase (HDAC) inhibitors in regulating sGC1 and -1 expression in human breast cancer MDA-MB-231 and MDA-MB-468 cell lines. The class I HDAC inhibitors increased the expression of sGC1 more than sGC1. Transient overexpression of HDAC3, but not HDAC1 or HDAC2, significantly reduced sGC1 mRNA. Chromatin immunoprecipitation assay confirmed an enhanced binding of HDAC3 to the sGC1 proximal promoter, which could be reversed by panobinostat (LBH-589) treatment. Mutations at the CCAAT binding sequence, a major element regulating sGC1 expression, markedly reduced the efficacy of LBH-589 in augmenting sGC1 promoter activity. LBH-589 markedly enhanced the binding of nuclear transcription factor Y, subunit , to the sGC1 promoter (CCAAT binding sequence). In summary, HDAC3 is an endogenous antagonist of sGC1 expression. Inhibition of HDAC3 with targeted therapy could benefit treatment of the diseases associated with sGC1 down-regulation and/or deficiency such as cancer and several vascular-related diseases.Sotolongo, A., Monica, F. Z., Kots, A., Xiao, H., Liu, J., Seto, E., Bian, K., Murad, F. Epigenetic regulation of soluble guanylate cyclase (sGC) 1 in breast cancer cells. (AU)

• Processo FAPESP: 13/02246-7 - Avaliação dos efeitos do acúmulo de GMPc em linhagens celulares de tumores de pâncreas e pulmão
• Beneficiário: Fabíola Taufic Monica Iglesias
• Modalidade de apoio: Bolsas no Exterior - Pesquisa