EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer
| العنوان: | EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer |
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| المؤلفون: | Laura Curti, Andrea Rinaldi, Marita Zoma, Sarah N. Mapelli, Jacopo Sgrignani, Jessica Merulla, Aleksandra Kokanovic, Andrea Cavalli, Carlo V. Catapano, Abhishek Mitra, Dheeraj Shinde, Giada Sandrini, Alessia Cacciatore, D. Albino, Gianluca Civenni, Giovanna Chiorino, Giuseppina M. Carbone, Paolo Kunderfranco |
| المصدر: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-19 (2021) |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Oncogene Proteins, Fusion, genetic structures, Protein Conformation, General Physics and Astronomy, Fusion gene, Mice, Prostate cancer, 0302 clinical medicine, Mice, Knockout, Oncogene Proteins, Multidisciplinary, Serine Endopeptidases, EZH2, Methylation, Gene Expression Regulation, Neoplastic, Oncology, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Epigenetics, Erg, Science, Adenocarcinoma, Biology, TMPRSS2, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Transcriptional Regulator ERG, medicine, Animals, PTEN, Enhancer of Zeste Homolog 2 Protein, Lysine, Prostatic Neoplasms, Cancer, General Chemistry, medicine.disease, eye diseases, 030104 developmental biology, Trans-Activators, Cancer research, biology.protein, sense organs, Protein Processing, Post-Translational, Sequence Alignment, Transcription Factors |
| الوصف: | The TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer. However, its role in disease progression is still unclear. In this study, we uncover an important mechanism promoting ERG oncogenic activity. We show that ERG is methylated by Enhancer of zest homolog 2 (EZH2) at a specific lysine residue (K362) located within the internal auto-inhibitory domain. Mechanistically, K362 methylation modifies intra-domain interactions, favors DNA binding and enhances ERG transcriptional activity. In a genetically engineered mouse model of ERG fusion-positive prostate cancer (Pb-Cre4 Pten flox/flox Rosa26-ERG, ERG/PTEN), ERG K362 methylation is associated with PTEN loss and progression to invasive adenocarcinomas. In both ERG positive VCaP cells and ERG/PTEN mice, PTEN loss results in AKT activation and EZH2 phosphorylation at serine 21 that favors ERG methylation. We find that ERG and EZH2 interact and co-occupy several sites in the genome forming trans-activating complexes. Consistently, ERG/EZH2 co-regulated target genes are deregulated preferentially in tumors with concomitant ERG gain and PTEN loss and in castration-resistant prostate cancers. Collectively, these findings identify ERG methylation as a post-translational modification sustaining disease progression in ERG-positive prostate cancers. Although the TMPRSS2-ERG gene fusion is the most common alteration in human prostate cancer, its involvement in disease progression remains unclear. Here, the authors demonstrate that ERG is methylated by Enhancer of zest homolog 2 leading to enhanced transcriptional and oncogenic activity. |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3f98e95b846dba51d721e234a0713874Test https://doi.org/10.1038/s41467-021-24380-6Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3f98e95b846dba51d721e234a0713874 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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