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Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer

2019; Cell Press; Volume: 30; Issue: 2 Linguagem: Inglês

10.1016/j.cmet.2019.05.004

1932-7420

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

Epigenetics and DNA Methylation

Summary 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.