• MeSH
• mobilní aplikace MeSH
• neziskové organizace MeSH
• primární prevence metody   trendy   MeSH

• MeSH
• mobilní aplikace * trendy   MeSH
• preventivní lékařství metody   MeSH
• primární prevence * organizace a řízení   trendy   MeSH
• Publikační typ
• rozhovory MeSH

• Publikační typ
• abstrakt z konference MeSH

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.

• MeSH
• androgenní receptory genetika   MeSH
• azacytidin aplikace a dávkování   analogy a deriváty   MeSH
• epigenomika MeSH
• histondeacetylasy genetika   MeSH
• inhibitory histondeacetylas aplikace a dávkování   MeSH
• kyselina máselná aplikace a dávkování   MeSH
• lidé MeSH
• metylace DNA účinky léků   MeSH
• nádorové buněčné linie MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   genetika   patologie   MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese u nádorů MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Androgen receptor (AR) expression in prostate cancer (CaP) cells varies due to the multiple changes including epigenetic modifications such as DNA methylation and histone deacetylation. DNA methyltransferase and histone deacetylase inhibitors are promising for the treatment of CaP. The aim of our study was to analyze the 5-aza-2'-deoxycytidine (Aza‑dC) and sodium butyrate (NaB) effects on CaP cells with modified AR gene expression. The androgen-independent human prostate cancer cell lines PC3 (lacking a functional AR) and DU145 (strongly limited expression due to methylations in the AR gene) were used. PCR of bisulfite-modified DNA and RT-PCR with bisulfite-sequencing were used for AR gene analysis of DU145 and PC3 cells following their treatment with Aza-dC and/or NaB. Re-acetylated histones around the AR gene were detected by conventional PCR of immunoprecipitated DNA obtained from treated cells. In both cell lines without the AR expression, the combined treatment was followed with significant decrease of cell viability. The co-treatment of DU145 cells caused site-specific demethylation in the AR promoter region followed by gene re-expression and increased acetylation in histones H3 and H4. The co-treatment with Aza-dC and NaB was the most effective in demethylation and re-expression of the AR gene. In the AR gene promoter, the location and density of deme-thylated CpGs indicated the existence of distinct promoter hot spot that could be a target of AR gene inactivation therapy of CaP patients during androgen deprivation.

• MeSH
• 5' nepřekládaná oblast MeSH
• acetylace účinky léků   MeSH
• androgenní receptory biosyntéza   genetika   metabolismus   MeSH
• androgeny genetika   metabolismus   MeSH
• azacytidin analogy a deriváty   farmakologie   MeSH
• DNA genetika   MeSH
• histondeacetylasy genetika   metabolismus   MeSH
• histony genetika   metabolismus   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• kyselina máselná farmakologie   MeSH
• lidé MeSH
• methyltransferasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• metylace DNA účinky léků   MeSH
• nádorové buněčné linie MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   enzymologie   genetika   metabolismus   MeSH
• promotorové oblasti (genetika) účinky léků   genetika   MeSH
• viabilita buněk účinky léků   genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Sodium butyrate, as a naturally occurring inhibitor of histone deacetylases (HDACI), is a non-toxic agent, with an ability to change histone acetylation and expression of large number genes. This study shows different effects of sodium butyrate on expression and transcription activity of the androgen receptor in cancer (LNCaP, C4-2) and normal (RWPE-1) prostate cells. Moreover, we studied the coregulator expressions and histone acetylation alteration in cancer and normal cells. Coregulators, coactivators as well as corepressors, play an important role in AR-mediated growth and progression of prostate cancer. There is a competition between coactivators and corepressors for binding on the AR and therefore the changes in coregulators expression and ratio could be important for prostate cancer survival. Our study was focused on two coregulators, SMRT and p300, which interact with AR in multiprotein complex and affect the AR transcription activity. Our data indicate that sodium butyrate has an effect on AR coregulators expression, transcription activity and histone acetylation in cancer cells, but there is only minimal effect in normal cells. In addition, the results of changes in acetylation level on lysine residues of histone H4 after sodium butyrate treatment confirm its epigenetic effect on prostate cancer cells.

• MeSH
• acetylace MeSH
• androgenní receptory genetika   metabolismus   MeSH
• buněčné linie MeSH
• histony metabolismus   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• kyselina máselná farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty metabolismus   MeSH
• prostata cytologie   MeSH
• prostatický specifický antigen metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH