Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer.
Publication/Presentation Date
11-8-2016
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.
Volume
7
Issue
45
First Page
72395
Last Page
72414
ISSN
1949-2553
Published In/Presented At
Oran, A. R., Adams, C. M., Zhang, X. Y., Gennaro, V. J., Pfeiffer, H. K., Mellert, H. S., Seidel, H. E., Mascioli, K., Kaplan, J., Gaballa, M. R., Shen, C., Rigoutsos, I., King, M. P., Cotney, J. L., Arnold, J. J., Sharma, S. D., Martinez-Outschoorn, U. E., Vakoc, C. R., Chodosh, L. A., Thompson, J. E., … McMahon, S. B. (2016). Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer. Oncotarget, 7(45), 72395–72414. https://doi.org/10.18632/oncotarget.11718
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
27590350
Department(s)
Administration and Leadership
Document Type
Article