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Oncotarget. 2016 Nov 8;7(45):72395-72414. doi: 10.18632/oncotarget.11718.

Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer.

Author information

1
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
2
Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, PA, USA.
3
Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
4
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
5
Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY, USA.
6
Department of Biochemistry, Thomas Jefferson University, Philadelphia, PA, USA.
7
Genetics and Genome Sciences, University of Connecticut Health, Farmington, CT, USA.
8
Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
9
Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA,USA.
11
Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
12
Department of Genetics, Yale School of Medicine, New Haven, CT, USA.

Abstract

Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production. Fortuitously, MYC-dependent tumor cell death can be induced by inhibiting the mitochondrial gene expression pathway using a variety of strategies, including treatment with FDA-approved antibiotics. In vivo studies using a mouse model of Burkitt's Lymphoma provide pre-clinical evidence that these antibiotics can successfully block progression of MYC-dependent tumors.

KEYWORDS:

MYC; mitochondria; mitochondrial gene expression; synthetic lethality; tigecycline

PMID:
27590350
PMCID:
PMC5340124
DOI:
10.18632/oncotarget.11718
[Indexed for MEDLINE]
Free PMC Article

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