Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer
View/ Open
Author
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, Ubaldo E.
Vakoc, Christopher R.
Chodosh, Lewis A.
Thompson, James E.
Cameron, Craig E.
Shadel, Gerald S.
Eischen, Christine M.
McMahon, Steven B.
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.18632/oncotarget.11718Metadata
Show full item recordCitation
Oran, A. R., C. M. Adams, X. Zhang, V. J. Gennaro, H. K. Pfeiffer, H. S. Mellert, H. E. Seidel, et al. 2016. “Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer.” Oncotarget 7 (45): 72395-72414. doi:10.18632/oncotarget.11718. http://dx.doi.org/10.18632/oncotarget.11718.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340124/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:32071988
Collections
- HMS Scholarly Articles [17922]
Contact administrator regarding this item (to report mistakes or request changes)