Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer
| Autor: | 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 |
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| Přispěvatelé: | 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) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
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 |
| Zdroj: | 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⟩ |
| ISSN: | 1550-4131 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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