c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks
Prostate cancer (PCa) is the most common non-cutaneous cancer in men. The androgen receptor (AR), a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to b...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-04-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396417301494 |
| _version_ | 1818537432082022400 |
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| author | Stefan J. Barfeld Alfonso Urbanucci Harri M. Itkonen Ladan Fazli Jessica L. Hicks Bernd Thiede Paul S. Rennie Srinivasan Yegnasubramanian Angelo M. DeMarzo Ian G. Mills |
| author_facet | Stefan J. Barfeld Alfonso Urbanucci Harri M. Itkonen Ladan Fazli Jessica L. Hicks Bernd Thiede Paul S. Rennie Srinivasan Yegnasubramanian Angelo M. DeMarzo Ian G. Mills |
| author_sort | Stefan J. Barfeld |
| collection | DOAJ |
| description | Prostate cancer (PCa) is the most common non-cutaneous cancer in men. The androgen receptor (AR), a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to be altered in patients and to influence AR activity. Amongst these, the oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies and elevated protein levels of c-Myc are commonly observed in PCa. Its impact on AR activity, however, remains elusive. In this study, we assessed the impact of c-Myc overexpression on AR activity and transcriptional output in a PCa cell line model and validated the antagonistic effect of c-MYC on AR-targets in patient samples. We found that c-Myc overexpression partially reprogrammed AR chromatin occupancy and was associated with altered histone marks distribution, most notably H3K4me1 and H3K27me3. We found c-Myc and the AR co-occupy a substantial number of binding sites and these exhibited enhancer-like characteristics. Interestingly, c-Myc overexpression antagonised clinically relevant AR target genes. Therefore, as an example, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 (alias PSA, prostate specific antigen), and Glycine N-Methyltransferase (GNMT), in patient samples. Our findings provide unbiased evidence that MYC overexpression deregulates the AR transcriptional program, which is thought to be a driving force in PCa. |
| first_indexed | 2024-12-11T18:50:40Z |
| format | Article |
| id | doaj.art-9991520fd4b04e2080ac059491b62c2d |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-11T18:50:40Z |
| publishDate | 2017-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-9991520fd4b04e2080ac059491b62c2d2022-12-22T00:54:19ZengElsevierEBioMedicine2352-39642017-04-0118C839310.1016/j.ebiom.2017.04.006c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene NetworksStefan J. Barfeld0Alfonso Urbanucci1Harri M. Itkonen2Ladan Fazli3Jessica L. Hicks4Bernd Thiede5Paul S. Rennie6Srinivasan Yegnasubramanian7Angelo M. DeMarzo8Ian G. Mills9Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, NorwayCentre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, NorwayCentre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, NorwayThe Vancouver Prostate Centre, University of British Columbia, CanadaDepartment of Biosciences, University of Oslo, Oslo, NorwayDepartment of Biosciences, University of Oslo, Oslo, NorwayThe Vancouver Prostate Centre, University of British Columbia, CanadaSidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, NorwayProstate cancer (PCa) is the most common non-cutaneous cancer in men. The androgen receptor (AR), a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to be altered in patients and to influence AR activity. Amongst these, the oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies and elevated protein levels of c-Myc are commonly observed in PCa. Its impact on AR activity, however, remains elusive. In this study, we assessed the impact of c-Myc overexpression on AR activity and transcriptional output in a PCa cell line model and validated the antagonistic effect of c-MYC on AR-targets in patient samples. We found that c-Myc overexpression partially reprogrammed AR chromatin occupancy and was associated with altered histone marks distribution, most notably H3K4me1 and H3K27me3. We found c-Myc and the AR co-occupy a substantial number of binding sites and these exhibited enhancer-like characteristics. Interestingly, c-Myc overexpression antagonised clinically relevant AR target genes. Therefore, as an example, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 (alias PSA, prostate specific antigen), and Glycine N-Methyltransferase (GNMT), in patient samples. Our findings provide unbiased evidence that MYC overexpression deregulates the AR transcriptional program, which is thought to be a driving force in PCa.http://www.sciencedirect.com/science/article/pii/S2352396417301494Prostate cancerGlycine N-Methyltransferase (GNMT)Chromatin immunoprecipitation exonuclease (ChIP-exo)Androgen receptorc-MycDNA damage |
| spellingShingle | Stefan J. Barfeld Alfonso Urbanucci Harri M. Itkonen Ladan Fazli Jessica L. Hicks Bernd Thiede Paul S. Rennie Srinivasan Yegnasubramanian Angelo M. DeMarzo Ian G. Mills c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks EBioMedicine Prostate cancer Glycine N-Methyltransferase (GNMT) Chromatin immunoprecipitation exonuclease (ChIP-exo) Androgen receptor c-Myc DNA damage |
| title | c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks |
| title_full | c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks |
| title_fullStr | c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks |
| title_full_unstemmed | c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks |
| title_short | c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks |
| title_sort | c myc antagonises the transcriptional activity of the androgen receptor in prostate cancer affecting key gene networks |
| topic | Prostate cancer Glycine N-Methyltransferase (GNMT) Chromatin immunoprecipitation exonuclease (ChIP-exo) Androgen receptor c-Myc DNA damage |
| url | http://www.sciencedirect.com/science/article/pii/S2352396417301494 |
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