المؤلفون: A. Cacciatore, G. Sandrini, C. Musumeci, L. Guarrera, D. Albino, M. Bolis, C.V. Catapano, G.M. Carbone

المصدر: European Urology. 83:S1671

مصطلحات موضوعية: Urology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::701dc2a1121a61639571efb12dcabbb3Test
https://doi.org/10.1016/s0302-2838Test(23)01195-8

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: L'Houcine Ouafik, Roberto Bosotti, D. Albino, Alyssa Paganoni, Simona Rossi, Martina Marchetti, Esteban Cvitkovic, Shusil Pandit, Giuseppina M. Carbone, Gianluca Civenni, Maria E. Riveiro, Abhishek Mitra, Martina Giurdanella, Marco Losa, Carlo V. Catapano, Sarah N. Mapelli, Sarah Mackenzie, Ramiro Vázquez, Keyvan Rezai, Gioacchino D'Ambrosio, Sara Allegrini, Diego Morone, Andrea Rinaldi, Andrea Timpanaro, Jessica Merulla, Luca Vierling, Enrica Mira-Catò, Rocco D'Antuono

المساهمون: Università della Svizzera italiana = University of Italian Switzerland (USI), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Institute for Research in Biomedicine [Ticino, Switzerland], Institute for Research in Biomedicine, Scuola Universitaria Professionale della Svizzera italiana, CRLCC René Huguenin, IRCCS Multimedica, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de Transfert d’Oncologie Biologique, APHM, Hôpital Nord, Hôpital Nord [CHU - APHM], Oncology Therapeutic Development, Oncoethix SA, Merck & Co. Inc, Université de Lausanne (UNIL)

المصدر: Cell Metabolism
Cell Metabolism, 2019, 30 (2), pp.303-318.e6. ⟨10.1016/j.cmet.2019.05.004⟩
Cell Metabolism, Elsevier, 2019, 30 (2), pp.303-318.e6. ⟨10.1016/j.cmet.2019.05.004⟩

مصطلحات موضوعية: 0301 basic medicine, Senescence, MFF, cancer stem cells, BRD4, Mitochondrial fission factor, Physiology, bromodomain and extra-terminal domain proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Cancer stem cell, mitochondrial fission factor, medicine, Epigenetics, BET inhibitors, Molecular Biology, Gene knockdown, mitochondrial fission, Cell Biology, medicine.disease, prostate cancer, mitochondrial dynamics, 3. Good health, 030104 developmental biology, Cancer research, Mitochondrial fission, OTX015/MK-8628, 030217 neurology & neurosurgery

الوصف: International audience; Cancer stem cells (CSCs) contribute to disease progression and treatment failure in human cancers. The balance among self-renewal, differentiation, and senescence determines the expansion or progressive exhaustion of CSCs. Targeting these processes might lead to novel anticancer therapies. Here, we uncover a novel link between BRD4, mitochondrial dynamics, and self-renewal of prostate CSCs. Targeting BRD4 by genetic knockdown or chemical inhibitors blocked mitochondrial fission and caused CSC exhaustion and loss of tumorigenic capability. Depletion of CSCs occurred in multiple prostate cancer models, indicating a common vulnerability and dependency on mitochondrial dynamics. These effects depended on rewiring of the BRD4-driven transcription and repression of mitochondrial fission factor (Mff). Knockdown of Mff reproduced the effects of BRD4 inhibition, whereas ectopic Mff expression rescued prostate CSCs from exhaustion. This novel concept of targeting mitochondrial plasticity in CSCs through BRD4 inhibition provides a new paradigm for developing more effective treatment strategies for prostate cancer.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d07433ac2a228a36fec1998a862422beTest
https://hal-amu.archives-ouvertes.fr/hal-02483099Test

المؤلفون: Rui Henrique, Giuseppina M. Carbone, D. Albino, Carmen Jerónimo, M. Pecoraro, D.O. Temilola, Dheeraj Shinde, L.F. Zerbini, A. Cacciatore, C.V. Catapano, R. Geiger, R.P. Mestre, V. Uboldi, L. Barile, M. Wium, R. Valzelli, G. Sandrini

المصدر: European Urology. 79:S597

مصطلحات موضوعية: Prostate cancer, business.industry, Urology, Cancer research, Medicine, business, medicine.disease, Extracellular vesicles

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::88966871e896b9dca8c24f788fa54735Test
https://doi.org/10.1016/s0302-2838Test(21)00811-3

المؤلفون: Dheeraj Shinde, Sarah N. Mapelli, Paula Costales, Jessica Merulla, Giuseppina M. Carbone, Marita Zoma, Azzurra Mutti, D. Albino, Carlo V. Catapano, Gianluca Civenni, Jhudit Pérez-Escuredo, Francisco Morís, Aleksandra Kokanovic

المصدر: European urology oncology. 2(4)

مصطلحات موضوعية: Male, genetic structures, Sp1 Transcription Factor, Urology, 030232 urology & nephrology, Mice, Transgenic, Fusion gene, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Transcriptional Regulator ERG, Cancer stem cell, Cell Line, Tumor, Medicine, PTEN, Animals, Humans, Radiology, Nuclear Medicine and imaging, biology, business.industry, PTEN Phosphohydrolase, Prostatic Neoplasms, Plicamycin, medicine.disease, Oncology, Tumor progression, 030220 oncology & carcinogenesis, Knockout mouse, Cancer cell, Cancer research, biology.protein, Neoplastic Stem Cells, Surgery, business, Reprogramming

الوصف: Background The TMPRSS2-ERG gene fusion is the most frequent genetic rearrangement in prostate cancers and results in broad transcriptional reprogramming and major phenotypic changes. Interaction and cooperation of ERG and SP1 may be instrumental in sustaining the tumorigenic and metastatic phenotype and could represent a potential vulnerability in ERG fusion–positive tumors. Objective To test the activity of EC-8042, a compound able to block SP1, in cellular and mouse models of ERG-positive prostate cancer. Design, setting, and participants We evaluated the activity of EC-8042 in cell cultures and ERG/PTEN transgenic/knockout mice that provide reliable models for testing novel therapeutics in this specific disease context. Using a new protocol to generate tumor spheroids from ERG/PTEN mice, we also examined the effects of EC-8042 on tumor-propagating stem-like cancer cells with high self-renewal and tumorigenic capabilities. Outcome measurements and statistical analysis The efficacy of EC-8042 was determined by measuring the proliferative capacity and target gene expression in cell cultures, invasive and metastatic capabilities in chick chorioallantoic membrane assays, and tumor development in mice. Significance was determined using statistical test. Results and limitations EC-8042 blocked transcription of ERG-regulated genes and reverted the invasive and metastatic phenotype of VCaP cells. EC-8042 blocked the expansion of stem-like tumor cells in tumor spheroids from VCaP cells and mouse-derived tumors. In ERG/PTEN mice, systemic treatment with EC-8042 inhibited ERG-regulated gene transcription, tumor progression, and tumor-propagating stem-like tumor cells. Conclusions Our data support clinical testing of EC-8042 for the treatment of ERG-positive prostate cancer in precision medicine approaches. Patient summary In this study, EC-8042, a novel compound with a favorable pharmacological and toxicological profile, exhibited relevant activity in cell cultures and in vivo in a genetically engineered mouse model that closely recapitulates the features of clinically aggressive ERG-positive prostate cancer. Our data indicate that further evaluation of EC-8042 in clinical trials is warranted.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9c0b41c38e51a8155911e66f58b22b74Test
https://pubmed.ncbi.nlm.nih.gov/31277777Test

المؤلفون: Carlo V. Catapano, Carmen Jerónimo, A. Sturchler, Mariangela Garofalo, Dheeraj Shinde, Vera Constâncio, Giuseppina M. Carbone, Rui Henrique, D. Albino, M. Falcione, Annalisa Grimaldi, Jessica Merulla, V. Uboldi, Gianluca Civenni, A. Cacciatore

المصدر: European Urology Supplements. 18:e3051

مصطلحات موضوعية: medicine.anatomical_structure, business.industry, Prostate, Urology, Cancer research, Medicine, business, Carcinogenesis, medicine.disease_cause

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::c70cffdd7689a175d3d3c06062f4cc95Test
https://doi.org/10.1016/s1569-9056Test(19)33300-7

المؤلفون: Carlo V. Catapano, R. Vasquez, R. Migheli, D. Albino, L. Vierling, A. Kokanovic, A. Timpanaro, S. Pandit, Dheeraj Shinde, E. Sorrenti, Gianluca Civenni, Jessica Merulla, Giuseppina M. Carbone, M. Giurdanella

المصدر: European Urology Supplements. 18:e3109

مصطلحات موضوعية: Prostate cancer, business.industry, Urology, Cancer research, Medicine, Stem cell, Self renewal, business, medicine.disease, Reprogramming

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::01b7c300db8fd07ffcc3ea057f69d63bTest
https://doi.org/10.1016/s1569-9056Test(19)33354-8

المؤلفون: Gianluca Civenni, D. Albino, A. Kokanovic, Marita Zoma, A. Zoma, Giuseppina M. Carbone, Carlo V. Catapano, Dheeraj Shinde

المصدر: European Urology Supplements. 18:e346

مصطلحات موضوعية: law, business.industry, Urology, Cancer research, Suppressor, Medicine, business, TMPRSS2, Erg, law.invention

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::ce49f8f7769aa1060fe83f812c562ef0Test
https://doi.org/10.1016/s1569-9056Test(19)30258-1

المؤلفون: D. Albino, Dheeraj Shinde, Gianluca Civenni, M. Falcione, Jessica Merulla, Carlo V. Catapano, Giuseppina M. Carbone

المصدر: European Urology Supplements. 18:e70

مصطلحات موضوعية: medicine.anatomical_structure, business.industry, Prostate, Urology, Medicine, business, Carcinogenesis, medicine.disease_cause, Extracellular vesicles, Microvesicles, Cell biology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::8b7c954eba53b4b63633bb6a17d50edfTest
https://doi.org/10.1016/s1569-9056Test(19)30053-3

المؤلفون: Giuseppina M. Carbone, F. Moris, Marita Zoma, A. Kokanovic, P. Costales, Dheeraj Shinde, D. Albino, Gianluca Civenni, Carlo V. Catapano, S. Mosole, S.N. Mapelli

المصدر: European Urology Supplements. 17:e2487

مصطلحات موضوعية: Transcriptome, medicine.anatomical_structure, Prostate, business.industry, Urology, Cancer research, medicine, Epigenetics, business, Reprogramming, Erg

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::157d221c196d8d1207a4c8b31dfcec1bTest
https://doi.org/10.1016/s1569-9056Test(18)32972-5