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)

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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3f98e95b846dba51d721e234a0713874Test
https://doi.org/10.1038/s41467-021-24380-6Test

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

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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::f4769d647beda5867b3d8546e148d6d1Test
https://doi.org/10.1158/1538-7445.am2016-lb-152Test

المؤلفون: Sergio Marchini, Chiara Romualdi, Duccio Cavalieri, Giovanna Chiorino, Paola Ostano, Eugenio Erba, Ilaria Fuso Nerini, Luca Beltrame, Sarah Uboldi, Daniela D'Angelo, Maurizio D'Incalci, Enrica Calura

المصدر: PLoS ONE
PLoS ONE, Vol 7, Iss 4, p e35423 (2012)

مصطلحات موضوعية: Identification, systems biology, cancer, anti-tumor compound, sarcoma, trabectedin, miRNA, gene expression, regulatory network, Transcription, Genetic, Microarrays, Cancer Treatment, lcsh:Medicine, Expression, Fusion gene, Tetrahydroisoquinolines, Bone and Soft Tissue Sarcomas, lcsh:Science, Trabectedin, Genetics, Regulation of gene expression, Multidisciplinary, ABL, Systems Biology, Genomics, Cell cycle, Phase II, Liposarcoma, Myxoid, Neoplasm Proteins, Oncology, Medicine, Mechanism, medicine.drug, Research Article, Cells, Ecteinascidin-743, Dioxoles, Biology, Liposarcoma, Ovarian cancer, Cell Line, Tumor, medicine, Humans, RNA, Messenger, Antineoplastic Agents, Alkylating, Platinum, Regulatory Networks, Myxoid liposarcoma, Gene Expression Profiling, lcsh:R, Computational Biology, Cancers and Neoplasms, ET-743, Chemotherapy and Drug Treatment, medicine.disease, Gene expression profiling, MicroRNAs, Genes, Drug Resistance, Neoplasm, Cancer research, lcsh:Q, Genome Expression Analysis

الوصف: Trabectedin, a new antitumor compound originally derived from a marine tunicate, is clinically effective in soft tissue sarcoma. The drug has shown a high selectivity for myxoid liposarcoma, characterized by the translocation t(12;16)(q13; p11) leading to the expression of FUS-CHOP fusion gene. Trabectedin appears to act interfering with mechanisms of transcription regulation. In particular, the transactivating activity of FUS-CHOP was found to be impaired by trabectedin treatment. Even after prolonged response resistance occurs and thus it is important to elucidate the mechanisms of resistance to trabectedin. To this end we developed and characterized a myxoid liposarcoma cell line resistant to trabectedin (402-91/ET), obtained by exposing the parental 402-91 cell line to stepwise increases in drug concentration. The aim of this study was to compare mRNAs, miRNAs and proteins profiles of 402-91 and 402-91/ET cells through a systems biology approach. We identified 3,083 genes, 47 miRNAs and 336 proteins differentially expressed between 402-91 and 402-91/ET cell lines. Interestingly three miRNAs among those differentially expressed, miR-130a, miR-21 and miR-7, harbored CHOP binding sites in their promoter region. We used computational approaches to integrate the three regulatory layers and to generate a molecular map describing the altered circuits in sensitive and resistant cell lines. By combining transcriptomic and proteomic data, we reconstructed two different networks, i.e. apoptosis and cell cycle regulation, that could play a key role in modulating trabectedin resistance. This approach highlights the central role of genes such as CCDN1, RB1, E2F4, TNF, CDKN1C and ABL1 in both pre- and post-transcriptional regulatory network. The validation of these results in in vivo models might be clinically relevant to stratify myxoid liposarcoma patients with different sensitivity to trabectedin treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e85c89525ec0593aa162935fc3293f3cTest
http://hdl.handle.net/2158/650728Test