Oncotarget

Priority Research Papers:

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

Amanda R. Oran, Clare M. Adams, Xiao-yong Zhang, Victoria J. Gennaro, Harla K. Pfeiffer, Hestia S. Mellert, Hans E. Seidel, Kirsten Mascioli, Jordan Kaplan, Mahmoud R. Gaballa, Chen Shen, Isidore Rigoutsos, Michael P. King, Justin L. Cotney, Jamie J. Arnold, Suresh D. Sharma, Ubaldo E. Martinez-Outschoorn, Christopher R. Vakoc, Lewis A. Chodosh, James E. Thompson, James E. Bradner, Craig E. Cameron, Gerald S. Shadel, Christine M. Eischen, Steven B. McMahon _

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Abstract

Amanda R. Oran1, Clare M. Adams1, Xiao-yong Zhang1, Victoria J. Gennaro1, Harla K. Pfeiffer1, Hestia S. Mellert2, Hans E. Seidel3, Kirsten Mascioli1, Jordan Kaplan1, Mahmoud R. Gaballa1, Chen Shen4,5, Isidore Rigoutsos1, Michael P. King6, Justin L. Cotney7, Jamie J. Arnold8, Suresh D. Sharma8, Ubaldo E. Martinez-Outschoorn1, Christopher R. Vakoc4, Lewis A. Chodosh3, James E. Thompson9, James E. Bradner10, Craig E. Cameron8, Gerald S. Shadel11,12, Christine M. Eischen1 and Steven B. McMahon1

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

Correspondence to:

Steven B. McMahon, email:

Keywords: MYC, mitochondria, mitochondrial gene expression, tigecycline, synthetic lethality

Received: June 08, 2016 Accepted: August 25, 2016 Published: August 31, 2016

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.

Author Information

Amanda R. Oran

Clare M. Adams

Xiao-yong Zhang

Victoria J. Gennaro

Harla K. Pfeiffer

Hestia S. Mellert

Hans E. Seidel

Kirsten Mascioli

Jordan Kaplan

Mahmoud R. Gaballa

Chen Shen

Isidore Rigoutsos

Michael P. King

Justin L. Cotney

Jamie J. Arnold

Suresh D. Sharma

Ubaldo E. Martinez-Outschoorn

Christopher R. Vakoc

Lewis A. Chodosh

James E. Thompson

James E. Bradner

Craig E. Cameron

Gerald S. Shadel

Christine M. Eischen

Steven B. McMahon
Primary Contact  _


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