Document Type
Article
Publication Date
8-31-2016
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.
Recommended Citation
Oran, Amanda R.; Adams, Clare M.; Zhang, Xiao-Yong; Gennaro, Victoria J.; Pfeiffer, Harla K.; Mellert, Hestia S.; Seidel, Hans E.; Mascioli, Kirsten; Kaplan, Jordan; Gaballa, Mahmoud R.; Shen, Chen; Rigoutsos, Isidore; King, Michael P.; Cotney, Justin L; Arnold, Jamie J.; Sharma, Suresh D.; Martinez-Outshoorn, Ubaldo E.; Vakoc, Christopher R.; Chodosh, Lewis A.; Thompson, James E.; Bradner, James E.; Cameron, Craig E.; Shadel, Gerald S.; Eischen, Christine M.; and McMahon, Steven B., "Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer." (2016). Department of Cancer Biology Faculty Papers. Paper 107.
https://jdc.jefferson.edu/cbfp/107
Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.
PubMed ID
27590350
Comments
This article has been peer reviewed. It is the author’s final published version in Oncotarget
Volume 7, Issue 45, August 2016, Pages 72395-72414.
The published version is available at DOI: 10.18632/oncotarget.11718. Copyright © Oran et al.