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

.https://www.ncbi.nlm.nih.gov/pubmed/31130467

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

INTRODUCTION

• Prostate cancer (PC) is the most common neoplasy in men and one of the main causes of cancer death in developed countries.

• Cancer stem cells (CSCs) are a small subset of cancer cells with stem-cell like properties. They contribute to treatment failure and relapse. Understanding the mechanisms which regulate their self-renewal, differentiation and senescence could lead to new therapeutic strategies.

• Mitochondrial reprogramming has important functions in CSCs. Mitochondrial dynamics control  asymmetric cell division, self-renewal, and the fate of stem cells. Fission and clearance of dysfunctional mitochondria avoid senescence and prevent stem cell exhaustion.

MAIN FINDINGS OF THE PAPER

• The authors uncover a novel link between the protein BRD4, mitochondrial dynamics and self-renewal of CSCs.

• Genetic knockdown of BRD4 or chemical inhibitors blocked mitochondrial fission and caused CSC exhaustion and loss of tumorigenic properties. This is mediated through the  inhibition of  mitochondrial fission factor (Mff) caused by BRD4 knockdown.

• Evidence for this is that suppression of Mff transcription reproduced the effects of BRD4 knockdown, whereas ectopic expression of Mff rescued CSCs from exhaustion. Therefore the authors conclude that targeting mitochondrial plasticity in CSCs is a promising avenue for new and more effective therapies.