Signaling through the androgen receptor (AR) plays a critical role in prostate cancer progression. The AR is a classical nuclear receptor (NR) providing a link between signaling molecule and transcription response. Histone deacetylase inhibitors (HDACI) have antiproliferative and proapoptotic effects on prostate cancer cells and their implication in silence AR signaling may have potential therapeutic use. We aimed to study the inhibitory effects of the corepressor SMRT (Silencing Mediator for Retinoid and Thyroid hormone receptors) which forms a complex together with nuclear receptor corepressor (N-CoR) and with histone deacetylase 3 (HDAC3) on AR activity. The androgen-sensitive prostate cancer cell line LNCaP and androgen-insensitive prostate cancer cell line C4-2 both AR-positive, and androgen-insensitive DU145 and PC3 prostate cancer cell lines were treated with two HDACIs, sodium butyrate (NaB) and/or trichostatin A (TSA). We amplified immunoprecipitated DNA by conventional PCR and in the following step we used the chromatin immunoprecipitation (ChIP) analysis coupled with quantitative PCR for monitoring NaB induced formation of AR-SMRT/N-CoR complex binding on the PSA promoter. The co-immunoprecipitation assay revealed increase in AR-SMRT formation in NaB treated cells. Simultaneously, the Western blot analysis showed a significant decrease in AR protein expression. Furthermore, we estimated the reduced presence of HDAC2 and HDAC3 proteins by NaB and TSA treatment in AR-negative DU145 cell line. In conclusion, the inhibitory effect of NaB on AR gene expression seems to be specific and unique for prostate cancer AR-positive cell lines and corresponds with its ability to stimulate AR-SMRT complex formation. We suggest that AR and SMRT/N-CoR corepressors may form a stable complex in vitro and NaB may facilitate the interaction between AR nuclear steroid receptor and SMRT corepressor protein.

• MeSH
• androgenní receptory genetika   metabolismus   MeSH
• butyráty metabolismus   farmakologie   terapeutické užití   MeSH
• časové faktory MeSH
• histondeacetylasa 2 metabolismus   MeSH
• histondeacetylasy metabolismus   MeSH
• imunoprecipitace MeSH
• inhibitory histondeacetylas terapeutické užití   MeSH
• korepresor 2 jaderného receptoru genetika   metabolismus   MeSH
• kyseliny hydroxamové metabolismus   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty farmakoterapie   genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• vazba proteinů genetika   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Molecular changes associated with malignancy are extremely complex. Early epigenetic events occurring in the common tumor types such as breast or prostate cancer might determine the subsequent genetic changes leading to tumor development and progression. Covalent modifications of histones play a major role as determiners of epigenetic information and are important in the regulation of gene expression. Acetylation generally correlates with transcriptional activation, while methylation can signal either activation or repression. However, little is known about the interplay of different epigenetic events. Steroid hormones regulate many cellular processes through signal transduction pathways that result in a variety of post-translational modifications. Such modifications can be triggered by steroid hormones in cooperation with coactivators(p160 family proteins, CBP, p300, p/CAF) and/or corepressors (N-Cor, SMRT, TZF). There is still much to learn about their regulation and the molecular and physiological consequences of these modifications.

• MeSH
• acetylace MeSH
• financování organizované MeSH
• histony metabolismus   MeSH
• lidé MeSH
• metylace MeSH
• pohlavní steroidní hormony metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• steroidní receptory fyziologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH

Annotation I: The study of ligand independent regulation of the androgen receptor. Annotation II: Clarify the role of corepressors in ligand independent regulation of androgen receptor. Annotation III: Clarify the role of histone deacetylases in ligand independent regulation of androgen receptor. Annotation IV: Investigate the effect of the inhibitor of histone deacetylation (NaB) and the inhibitor of DNA methylation (5-Aza-CdR) on transcriptional silencing of methylated gene.

Studium na ligandu nezávislé regulace androgenového receptoru. Objasnit úlohu korepresorů na ligandu nezávislé regulaci androgenového receptoru. Objasnit úlohu histonových deacetyláz na ligandu nezávislé regulaci androgenového receptoru. Sledovat efekt kombinace inhibitoru deacetyláz (NaB) a inhibitoru DNA metylace (5-Aza-CdR) u transkripčně neaktivního genu ZNF185.

• MeSH
• acetylace MeSH
• genetická transkripce MeSH
• histony chemie   MeSH
• metylace DNA MeSH
• nádorové buněčné linie MeSH
• nádory prostaty diagnóza   MeSH
• prostatický specifický antigen MeSH
• regulace genové exprese MeSH
• transkripční faktory MeSH
• umlčování genů MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• andrologie
• biologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR