Bromodomain and Extra-Terminal Family Proteins BRD2, BRD3, and BRD4 Contribute to H19-Dependent Transcriptional Regulation of Cell Adhesion Molecules, Modulating Metastatic Dissemination Program in Prostate Cancer
Background/Objectives: Metastatic prostate cancer (PCa) remains a major clinical challenge with limited therapeutic options. The long non-coding RNA <i>H19</i> has been implicated in regulating cell adhesion molecules and collective migration, key features of metastatic dissemination. Th...
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2025-04-01
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| author | Valeria Pecci Melissa Borsa Aurora Aiello Sara De Martino Luca Cis Cristian Ripoli Dante Rotili Francesco Pierconti Francesco Pinto Claudio Grassi Carlo Gaetano Antonella Farsetti Simona Nanni |
| author_facet | Valeria Pecci Melissa Borsa Aurora Aiello Sara De Martino Luca Cis Cristian Ripoli Dante Rotili Francesco Pierconti Francesco Pinto Claudio Grassi Carlo Gaetano Antonella Farsetti Simona Nanni |
| author_sort | Valeria Pecci |
| collection | DOAJ |
| description | Background/Objectives: Metastatic prostate cancer (PCa) remains a major clinical challenge with limited therapeutic options. The long non-coding RNA <i>H19</i> has been implicated in regulating cell adhesion molecules and collective migration, key features of metastatic dissemination. This study investigates the role of the Bromodomain and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 in the <i>H19</i>-dependent transcriptional regulation of cell adhesion molecules. Currently, the major effects of BET inhibitors require androgen receptor (AR) expression. Methods: <i>H19</i> was stably silenced in PC-3 (AR-null) and 22Rv1 (AR-positive) castration-resistant PCa cells. The cells were treated with the pan-BET inhibitors JQ1 and OTX015 or the BET degrader dBET6. In vivo, the effects of JQ1 were evaluated in xenograft mouse models. Chromatin immunoprecipitation (ChIP) and RNA-ChIP were used to assess BET protein recruitment and interaction with cell adhesion gene loci and <i>H19</i>. Organotypic slice cultures (OSCs) from fresh PCa surgical specimens were used as ex vivo models to validate transcriptional changes and BRD4 recruitment. Results: BET inhibition significantly reduced the expression of β4 integrin and E-cadherin and cell proliferation in both basal conditions, and following <i>H19</i> knockdown in PC-3 and 22Rv1 cells. These effects were mirrored in JQ1-treated tumor xenografts, which showed marker downregulation and tumor regression. ChIP assays revealed that BRD4, more than BRD2/3, was enriched on β4 integrin and E-cadherin promoters, especially in regions marked by H3K27ac. <i>H19</i> silencing markedly enhanced BRD4 promoter occupancy. RNA-ChIP confirmed a specific interaction between BRD4 and <i>H19</i>. These findings were validated in OSCs, reinforcing their clinical relevance. Conclusions: Our study demonstrates that BRD4 epigenetically regulates the <i>H19</i>-mediated transcriptional control of adhesion molecules involved in collective migration and metastatic dissemination. Importantly, these effects are independent of AR status, suggesting that targeting the <i>H19</i>/BRD4 axis may represent a promising therapeutic avenue for advanced PCa. |
| format | Article |
| id | doaj-art-7395c81b52ec4506b39bfa625f7d3129 |
| institution | Kabale University |
| issn | 2311-553X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
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| series | Non-Coding RNA |
| spelling | doaj-art-7395c81b52ec4506b39bfa625f7d31292025-08-20T03:29:40ZengMDPI AGNon-Coding RNA2311-553X2025-04-011133310.3390/ncrna11030033Bromodomain and Extra-Terminal Family Proteins BRD2, BRD3, and BRD4 Contribute to H19-Dependent Transcriptional Regulation of Cell Adhesion Molecules, Modulating Metastatic Dissemination Program in Prostate CancerValeria Pecci0Melissa Borsa1Aurora Aiello2Sara De Martino3Luca Cis4Cristian Ripoli5Dante Rotili6Francesco Pierconti7Francesco Pinto8Claudio Grassi9Carlo Gaetano10Antonella Farsetti11Simona Nanni12Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, ItalyDepartment of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, ItalyNational Research Council (CNR)-IASI, 00185 Rome, ItalyNational Research Council (CNR)-IASI, 00185 Rome, ItalyDepartment of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, ItalyFondazione “Policlinico Universitario A. Gemelli IRCCS”, 00168 Rome, ItalyDipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, 00185 Rome, ItalyFondazione “Policlinico Universitario A. Gemelli IRCCS”, 00168 Rome, ItalyFondazione “Policlinico Universitario A. Gemelli IRCCS”, 00168 Rome, ItalyFondazione “Policlinico Universitario A. Gemelli IRCCS”, 00168 Rome, ItalyLaboratory of Epigenetics, Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, ItalyNational Research Council (CNR)-IASI, 00185 Rome, ItalyDepartment of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, ItalyBackground/Objectives: Metastatic prostate cancer (PCa) remains a major clinical challenge with limited therapeutic options. The long non-coding RNA <i>H19</i> has been implicated in regulating cell adhesion molecules and collective migration, key features of metastatic dissemination. This study investigates the role of the Bromodomain and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 in the <i>H19</i>-dependent transcriptional regulation of cell adhesion molecules. Currently, the major effects of BET inhibitors require androgen receptor (AR) expression. Methods: <i>H19</i> was stably silenced in PC-3 (AR-null) and 22Rv1 (AR-positive) castration-resistant PCa cells. The cells were treated with the pan-BET inhibitors JQ1 and OTX015 or the BET degrader dBET6. In vivo, the effects of JQ1 were evaluated in xenograft mouse models. Chromatin immunoprecipitation (ChIP) and RNA-ChIP were used to assess BET protein recruitment and interaction with cell adhesion gene loci and <i>H19</i>. Organotypic slice cultures (OSCs) from fresh PCa surgical specimens were used as ex vivo models to validate transcriptional changes and BRD4 recruitment. Results: BET inhibition significantly reduced the expression of β4 integrin and E-cadherin and cell proliferation in both basal conditions, and following <i>H19</i> knockdown in PC-3 and 22Rv1 cells. These effects were mirrored in JQ1-treated tumor xenografts, which showed marker downregulation and tumor regression. ChIP assays revealed that BRD4, more than BRD2/3, was enriched on β4 integrin and E-cadherin promoters, especially in regions marked by H3K27ac. <i>H19</i> silencing markedly enhanced BRD4 promoter occupancy. RNA-ChIP confirmed a specific interaction between BRD4 and <i>H19</i>. These findings were validated in OSCs, reinforcing their clinical relevance. Conclusions: Our study demonstrates that BRD4 epigenetically regulates the <i>H19</i>-mediated transcriptional control of adhesion molecules involved in collective migration and metastatic dissemination. Importantly, these effects are independent of AR status, suggesting that targeting the <i>H19</i>/BRD4 axis may represent a promising therapeutic avenue for advanced PCa.https://www.mdpi.com/2311-553X/11/3/33long non-coding RNAmetastatic programepigeneticstranscription regulation |
| spellingShingle | Valeria Pecci Melissa Borsa Aurora Aiello Sara De Martino Luca Cis Cristian Ripoli Dante Rotili Francesco Pierconti Francesco Pinto Claudio Grassi Carlo Gaetano Antonella Farsetti Simona Nanni Bromodomain and Extra-Terminal Family Proteins BRD2, BRD3, and BRD4 Contribute to H19-Dependent Transcriptional Regulation of Cell Adhesion Molecules, Modulating Metastatic Dissemination Program in Prostate Cancer Non-Coding RNA long non-coding RNA metastatic program epigenetics transcription regulation |
| title | Bromodomain and Extra-Terminal Family Proteins BRD2, BRD3, and BRD4 Contribute to H19-Dependent Transcriptional Regulation of Cell Adhesion Molecules, Modulating Metastatic Dissemination Program in Prostate Cancer |
| title_full | Bromodomain and Extra-Terminal Family Proteins BRD2, BRD3, and BRD4 Contribute to H19-Dependent Transcriptional Regulation of Cell Adhesion Molecules, Modulating Metastatic Dissemination Program in Prostate Cancer |
| title_fullStr | Bromodomain and Extra-Terminal Family Proteins BRD2, BRD3, and BRD4 Contribute to H19-Dependent Transcriptional Regulation of Cell Adhesion Molecules, Modulating Metastatic Dissemination Program in Prostate Cancer |
| title_full_unstemmed | Bromodomain and Extra-Terminal Family Proteins BRD2, BRD3, and BRD4 Contribute to H19-Dependent Transcriptional Regulation of Cell Adhesion Molecules, Modulating Metastatic Dissemination Program in Prostate Cancer |
| title_short | Bromodomain and Extra-Terminal Family Proteins BRD2, BRD3, and BRD4 Contribute to H19-Dependent Transcriptional Regulation of Cell Adhesion Molecules, Modulating Metastatic Dissemination Program in Prostate Cancer |
| title_sort | bromodomain and extra terminal family proteins brd2 brd3 and brd4 contribute to h19 dependent transcriptional regulation of cell adhesion molecules modulating metastatic dissemination program in prostate cancer |
| topic | long non-coding RNA metastatic program epigenetics transcription regulation |
| url | https://www.mdpi.com/2311-553X/11/3/33 |
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