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

Details

Serval ID
serval:BIB_160F9BD5E05B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer
Journal
Cell Metabolism
Author(s)
Civenni Gianluca, Bosotti Roberto, Timpanaro Andrea, Vàzquez Ramiro, Merulla Jessica, Pandit Shusil, Rossi Simona, Albino Domenico, Allegrini Sara, Mitra Abhishek, Mapelli Sarah N., Vierling Luca, Giurdanella Martina, Marchetti Martina, Paganoni Alyssa, Rinaldi Andrea, Losa Marco, Mira-Catò Enrica, D'Antuono Rocco, Morone Diego, Rezai Keyvan, D'Ambrosio Gioacchino, Ouafik L'Houcine, Mackenzie Sarah, Riveiro Maria E., Cvitkovic Esteban, Carbone Giuseppina M., Catapano Carlo V.
ISSN
1932-7420 (Electronic))
ISSN-L
1550-4131
Publication state
Published
Issued date
08/2019
Peer-reviewed
Oui
Volume
30
Number
2
Pages
303-318.e6
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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.
Keywords
BET inhibitors, BRD4, MFF, OTX015/MK-8628, bromodomain and extra-terminal domain proteins, cancer stem cells, mitochondrial dynamics, mitochondrial fission, mitochondrial fission factor, prostate cancer
Pubmed
Web of science
Funding(s)
Swiss National Science Foundation
Create date
19/08/2019 12:54
Last modification date
20/10/2020 5:23
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