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

authors

• Civenni Gianluca
• Bosotti Roberto
• Timpanaro Andrea
• Vàzquez Ramiro
• Merulla Jessica
• Pandit Shusil
• Rossi Simona
• Albino Domenico
• Allegrini Sara
• Mitra Abhishek
• Mapelli Sarah
• Vierling Luca
• Giurdanella Martina
• Marchetti Martina
• Paganoni Alyssa
• Rinaldi Andréa
• Losa Marco
• Mira-Catò Enrica
• d'Antuono Rocco
• Morone Diego
• Rezaï Keyvan
• d'Ambrosio Gioacchino
• Ouafik L'Houcine
• Mackenzie Sarah
• Riveiro Maria
• Cvitkovic Esteban
• Carbone Giuseppina
• Catapano Carlo

keywords

• MFF
• OTX015/MK-8628
• Bromodomain and extra-terminal domain proteins
• Cancer stem cells
• Mitochondrial dynamics
• Mitochondrial fission
• Mitochondrial fission factor
• Prostate cancer
• BET inhibitors
• BRD4

abstract

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.

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