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

CIVENNI, GIANLUCA; BOSOTTI, ROBERTO; TIMPANARO, ANDREA; VÁZQUEZ, RAMIRO; MERULLA, JESSICA; PANDIT, SHUSIL; ROSSI, SIMONA; ALBINO, DOMENICO; ALLEGRINI, SARA; MITRA, ABHISHEK; MAPELLI, SARAH NATALIA; VIERLING, LUCA; GIURDANELLA, MARTINA; MARCHETTI, MARTINA; PAGANONI, ALYSSA; RINALDI, ANDREA; LOSA, MARCO; MIRA-CATÓ, ENRICA; D'ANTUONO, ROCCO; MORONE, DIEGO; REZAI, KEYVAN; D'AMBROSIO, GIOACCHINO; OUAFIK, L'HOUCINE; MACKENZIE, SARAH; RIVEIRO, MARÍA EUGENIA; CVITKOVIC, ESTEBAN; CARBONE, GIUSEPPINA M.; CATAPANO, CARLO V.

CELL METABOLISM

CELL PRESS

Lugar: United States; Año: 2019

1550-4131

Cancer stem cells (CSCs) contribute to disease progression and treatment failure in human cancers. The balance among self-renewal, differentiation, andsenescence determines the expansion or progressive exhaustion of CSCs. Targeting these processes might lead to novel anticancer therapies. Here,we uncover anovel link between BRD4, mitochondrial dynamics, and self-renewal of prostate CSCs. Targeting BRD4 by genetic knockdown or chemical inhibitors blockedmitochondrial fission and causedCSCexhaustion 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 prostateCSCs from exhaustion. This novel concept of targeting mitochondrial plasticity in CSCs through BRD4 inhibition provides a new paradigmfor developingmoreeffective treatment strategies for prostate cancer.