Novel Insights on the Role of Epigenetics in Androgen Receptor’s Expression in Prostate Cancer
The androgens/androgen receptor (AR) axis is the main therapeutic target in prostate cancer (PCa). However, while initially responsive, a subset of tumors loses AR expression through mechanisms putatively associated with epigenetic modifications. In this study, we assessed the link between the prese...
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MDPI AG
2023-10-01
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| Online Access: | https://www.mdpi.com/2218-273X/13/10/1526 |
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| author | Vânia Camilo Mariana Brütt Pacheco Filipa Moreira-Silva Gonçalo Outeiro-Pinho Vítor M. Gaspar João F. Mano C. Joana Marques Rui Henrique Carmen Jerónimo |
| author_facet | Vânia Camilo Mariana Brütt Pacheco Filipa Moreira-Silva Gonçalo Outeiro-Pinho Vítor M. Gaspar João F. Mano C. Joana Marques Rui Henrique Carmen Jerónimo |
| author_sort | Vânia Camilo |
| collection | DOAJ |
| description | The androgens/androgen receptor (AR) axis is the main therapeutic target in prostate cancer (PCa). However, while initially responsive, a subset of tumors loses AR expression through mechanisms putatively associated with epigenetic modifications. In this study, we assessed the link between the presence of CpG methylation in the 5′UTR and promoter regions of AR and loss of AR expression. Hence, we characterized and compared the methylation signature at CpG resolution of these regulatory regions in vitro, both at basal levels and following treatment with 5-aza-2-deoxycytidine (DAC) alone, or in combination with Trichostatin A (TSA). Our results showed heterogeneity in the methylation signature of AR negative cell lines and pinpointed the proximal promoter region as the most consistently methylated site in DU-145. Furthermore, this region was extremely resistant to the demethylating effects of DAC and was only significantly demethylated upon concomitant treatment with TSA. Nevertheless, no AR re-expression was detected at the mRNA or protein level. Importantly, after treatment, there was a significant increase in repressive histone marks at AR region 1 in DU-145 cells. Altogether, our data indicate that AR region 1 genomic availability is crucial for AR expression and that the inhibition of histone methyltransferases might hold promise for AR re-expression. |
| first_indexed | 2024-03-10T21:24:49Z |
| format | Article |
| id | doaj.art-c0e55395c7a34888b492be618a49ccf4 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T21:24:49Z |
| publishDate | 2023-10-01 |
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| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-c0e55395c7a34888b492be618a49ccf42023-11-19T15:50:30ZengMDPI AGBiomolecules2218-273X2023-10-011310152610.3390/biom13101526Novel Insights on the Role of Epigenetics in Androgen Receptor’s Expression in Prostate CancerVânia Camilo0Mariana Brütt Pacheco1Filipa Moreira-Silva2Gonçalo Outeiro-Pinho3Vítor M. Gaspar4João F. Mano5C. Joana Marques6Rui Henrique7Carmen Jerónimo8Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC) Raquel Seruca, R. Dr. António Bernardino de Almeida, 4200-072 Porto, PortugalCancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC) Raquel Seruca, R. Dr. António Bernardino de Almeida, 4200-072 Porto, PortugalCancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC) Raquel Seruca, R. Dr. António Bernardino de Almeida, 4200-072 Porto, PortugalCancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC) Raquel Seruca, R. Dr. António Bernardino de Almeida, 4200-072 Porto, PortugalCICECO—Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, PortugalCICECO—Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, PortugalGenetics Unit, Department of Pathology, Faculty of Medicine, University of Porto (FMUP), Alameda Prof. Hernâni Monteiro, 4200-319 Porto, PortugalCancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC) Raquel Seruca, R. Dr. António Bernardino de Almeida, 4200-072 Porto, PortugalCancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC) Raquel Seruca, R. Dr. António Bernardino de Almeida, 4200-072 Porto, PortugalThe androgens/androgen receptor (AR) axis is the main therapeutic target in prostate cancer (PCa). However, while initially responsive, a subset of tumors loses AR expression through mechanisms putatively associated with epigenetic modifications. In this study, we assessed the link between the presence of CpG methylation in the 5′UTR and promoter regions of AR and loss of AR expression. Hence, we characterized and compared the methylation signature at CpG resolution of these regulatory regions in vitro, both at basal levels and following treatment with 5-aza-2-deoxycytidine (DAC) alone, or in combination with Trichostatin A (TSA). Our results showed heterogeneity in the methylation signature of AR negative cell lines and pinpointed the proximal promoter region as the most consistently methylated site in DU-145. Furthermore, this region was extremely resistant to the demethylating effects of DAC and was only significantly demethylated upon concomitant treatment with TSA. Nevertheless, no AR re-expression was detected at the mRNA or protein level. Importantly, after treatment, there was a significant increase in repressive histone marks at AR region 1 in DU-145 cells. Altogether, our data indicate that AR region 1 genomic availability is crucial for AR expression and that the inhibition of histone methyltransferases might hold promise for AR re-expression.https://www.mdpi.com/2218-273X/13/10/1526prostate cancerandrogen receptorDNA methylationepigeneticstranscriptional repression |
| spellingShingle | Vânia Camilo Mariana Brütt Pacheco Filipa Moreira-Silva Gonçalo Outeiro-Pinho Vítor M. Gaspar João F. Mano C. Joana Marques Rui Henrique Carmen Jerónimo Novel Insights on the Role of Epigenetics in Androgen Receptor’s Expression in Prostate Cancer Biomolecules prostate cancer androgen receptor DNA methylation epigenetics transcriptional repression |
| title | Novel Insights on the Role of Epigenetics in Androgen Receptor’s Expression in Prostate Cancer |
| title_full | Novel Insights on the Role of Epigenetics in Androgen Receptor’s Expression in Prostate Cancer |
| title_fullStr | Novel Insights on the Role of Epigenetics in Androgen Receptor’s Expression in Prostate Cancer |
| title_full_unstemmed | Novel Insights on the Role of Epigenetics in Androgen Receptor’s Expression in Prostate Cancer |
| title_short | Novel Insights on the Role of Epigenetics in Androgen Receptor’s Expression in Prostate Cancer |
| title_sort | novel insights on the role of epigenetics in androgen receptor s expression in prostate cancer |
| topic | prostate cancer androgen receptor DNA methylation epigenetics transcriptional repression |
| url | https://www.mdpi.com/2218-273X/13/10/1526 |
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