Abstract LB-152: EZH2-induced lysine methylation and ERG-EZH2 genomic co-occupancy set the basis for extensive transcriptome reprogramming and prostate cancer progression
| العنوان: | Abstract LB-152: EZH2-induced lysine methylation and ERG-EZH2 genomic co-occupancy set the basis for extensive transcriptome reprogramming and prostate cancer progression |
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| المؤلفون: | Carlo V. Catapano, Laura Curti, Simona Rossi, Abhishek Mitra, Marita Zoma, Domenico Albino, Giuseppina M. Carbone, Dheeraj Shinde, Giovanna Chiorino, George N. Thalmann, Gianluca Civenni |
| المصدر: | Cancer Research. 76:LB-152 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Cancer Research, genetic structures, biology, Chromatin binding, EZH2, Cancer, macromolecular substances, medicine.disease_cause, medicine.disease, eye diseases, Fusion gene, Prostate cancer, Oncology, medicine, biology.protein, Cancer research, PTEN, sense organs, Carcinogenesis, Erg |
| الوصف: | The TMPRSS2-ERG gene fusion is found in about half of prostate tumors and represents one of the most frequent genetic rearrangements in human cancers. The gene fusion provides a mechanism for androgen-stimulated ERG over-expression and broad transcriptional reprogramming in prostate cancer. However, the biological impact of aberrant ERG expression on tumor initiation and progression is still unclear. ERG apparently requires additional co-factors to fully exert its oncogenic effects but the molecular details of these interactions are not defined yet. Understanding these mechanisms could have a huge impact on the clinical management of this disease. Enhancer of zest homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2 (PRC2) catalyzing histone H3 lysine 27 tri-methylation, is over-expressed in many human cancers and is associated with prostate cancer progression. In primary and metastatic prostate tumors ERG and EZH2 are frequently and concomitantly up-regulated. In this study we tested the hypothesis that EZH2 could act as a co-factor of ERG enhancing its transcriptional and oncogenic activity and identified a novel mechanism driving ERG activation and prostate cancer progression. We found that EZH2 physically interacts with ERG in ERG fusion positive cell lines and human tumors. Moreover, ERG/EZH2 co-occupied multiple genomic sites forming co-activator/co-repressor complexes and enabling massive transcriptional reprogramming. Expression of ERG/EZH2 co-occupied genes reflected the level of ERG activation, was preferentially deregulated in ERG-positive tumors and predicted clinical outcome. Furthermore, EZH2 catalyzed the methylation of ERG at a highly conserved lysine (K362) residue, which resulted in increased chromatin binding and transcriptional activity of ERG. PTEN deficiency and AKT activation promoted ERG methylation and ERG/EZH2 genomic co-occupancy along with a more aggressive and metastatic phenotype in ERG fusion positive cancer cells. Thus, this study identifies the ERG/EZH2 interaction and EZH2-induced ERG methylation as important elements promoting prostate tumorigenesis and at the center of cross-talks between the ERG gene fusion and PTEN deficiency in prostate cancer. Notably, these events were blocked effectively by pharmacological inhibitors of EZH2 providing the rationale for novel context-dependent therapeutic strategies in ERG positive prostate cancer. Citation Format: Giuseppina M. R. Carbone, Laura Curti, Marita Zoma, Abhishek Mitra, Dheeraj Shinde, Domenico Albino, Simona Rossi, Gianluca Civenni, George N. Thalmann, Giovanna Chiorino, Carlo Catapano. EZH2-induced lysine methylation and ERG-EZH2 genomic co-occupancy set the basis for extensive transcriptome reprogramming and prostate cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-152. |
| تدمد: | 1538-7445 0008-5472 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::f4769d647beda5867b3d8546e148d6d1Test https://doi.org/10.1158/1538-7445.am2016-lb-152Test |
| رقم الانضمام: | edsair.doi...........f4769d647beda5867b3d8546e148d6d1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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