title: Epigenetic modulation of AR gene expression in prostate cancer DU145 cells with the combination of sodium butyrate and 5'-Aza-2'-deoxycytidine.
abstract: The androgen receptor (AR) plays an essential role in the development and progression of prostate cancer. Castration-resistant prostate cancer (CRPC) is a consequence of androgen deprivation therapy. Unchecked CRPC followed by metastasis is lethal. Some CRPCs show decreased AR gene expression due to epigenetic mechanisms such as DNA methylation and histone deacetylation. The aim of this study was to epigenetically modulate the methylated state of the AR gene leading to targeted demethylation and AR gene expression in androgen-independent human prostate cancer DU145 cell line, representing the CRPC model with very low or undetectable AR levels. The cell treatment was based on single and combined applications of two epigenetic inhibitors, sodium butyrate (NaB) as histone deacetylases inhibitor and 5'-Aza-2'-deoxycytidine (Aza-dC) as DNA methyltransferases inhibitor. We found that the Aza-dC in combination with NaB may help reduce the toxicity of higher NaB concentrations in cancer cells. In normal RWPE-1 cells and even stronger in cancer DU145 cells, the combined treatment induced both AR gene expression on the mRNA level and increased histone H4 acetylation in AR gene promoter. Also activation and maintenance of G2/M cell cycle arrest and better survival in normal RWPE-1 cells compared to cancer DU145 cells were observed after the treatments. These results imply the selective toxicity effect of both inhibitors used and their potentially more effective combined use in the epigenetic therapy of prostate cancer patients.
authors: Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic.
authors: Barbora
authors: B
authors: Fialova
authors: Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic.
authors: Petra
authors: P
authors: Luzna
authors: Institute of Molecular and Translational Medicine, Palacky University Olomouc and University Hospital, Olomouc, Czech Republic.
authors: Jan
authors: J
authors: Gursky
authors: Institute of Molecular and Translational Medicine, Palacky University Olomouc and University Hospital, Olomouc, Czech Republic.
authors: Katerina
authors: K
authors: Langova
authors: Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic.
authors: Zdenek
authors: Z
authors: Kolar
authors: Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic.
authors: Katerina Smesny
authors: KS
authors: Trtkova
mesh_terms: D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D020148:Butyric Acid / Q000008:administration & dosage; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D057890:Epigenomics; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics*
chemical_list: C410798:AR protein, human; D056572:Histone Deacetylase Inhibitors; D011944:Receptors, Androgen; D020148:Butyric Acid; D000077209:Decitabine; D006655:Histone Deacetylases; D001374:Azacitidine