A MYC-Driven Change in Mitochondrial Dynamics Limits YAP/TAZ Function in Mammary Epithelial Cells and Breast Cancer

• Published in: Cancer cell 2015-12, Vol.28 (6), p.743-757
• Main Authors: von Eyss, Björn, Jaenicke, Laura A., Kortlever, Roderik M., Royla, Nadine, Wiese, Katrin E., Letschert, Sebastian, McDuffus, Leigh-Anne, Sauer, Markus, Rosenwald, Andreas, Evan, Gerard I., Kempa, Stefan, Eilers, Martin
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; AMP-Activated Protein Kinases - metabolism; Animals; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line; Cell Lineage; Computational Biology; Databases, Genetic; Enzyme Activation; Enzyme Induction; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Mammary Glands, Human - metabolism; Mammary Glands, Human - pathology; Mice, Transgenic; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Dynamics; Phenotype; Phospholipase D - biosynthesis; Phospholipase D - genetics; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA Interference; Signal Transduction; Time Factors; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Transfection; YAP-Signaling Proteins
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2015.10.013

In several developmental lineages, an increase in MYC expression drives the transition from quiescent stem cells to transit-amplifying cells. We show that MYC activates a stereotypic transcriptional program of genes involved in cell growth in mammary epithelial cells. This change in gene expression indirectly inhibits the YAP/TAZ co-activators, which maintain the clonogenic potential of these cells. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. MYC-dependent growth strains cellular energy resources and stimulates AMP-activated kinase (AMPK). PLD6 alters mitochondrial fusion and fission dynamics downstream of MYC. This change activates AMPK, which in turn inhibits YAP/TAZ. Mouse models and human pathological data show that MYC enhances AMPK and suppresses YAP/TAZ activity in mammary tumors. [Display omitted] •MYC represses YAP/TAZ-dependent transcription•MYC-dependent changes in mitochondrial dynamics inhibit YAP/TAZ•MYC activates AMPK downstream of changes in mitochondrial dynamics•Activation of AMPK disrupts the TEAD-YAP interaction in MYC-driven breast cancer Von Eyss et al. show that MYC induces PLD6 expression to promote mitochondrial fusion, leading to stimulation of AMPK. Activated AMPK then phosphorylates YAP to inhibit YAP/TAZ function. Both high MYC activity and elevated PLD6 expression correlate with poor prognosis of breast cancer patients.