@article{0b1783adb9c1401985c3b6609882b7c4,
title = "Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer",
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",
author = "Oran, {Amanda R.} and Adams, {Clare M.} and Zhang, {Xiao Yong} and Gennaro, {Victoria J.} and Pfeiffer, {Harla K.} and Mellert, {Hestia S.} and Seidel, {Hans E.} and Kirsten Mascioli and Jordan Kaplan and Gaballa, {Mahmoud R.} and Chen Shen and Isidore Rigoutsos and King, {Michael P.} and Cotney, {Justin L.} and Arnold, {Jamie J.} and Sharma, {Suresh D.} and Martinez-Outschoorn, {Ubaldo E.} and Vakoc, {Christopher R.} and Chodosh, {Lewis A.} and Thompson, {James E.} and Bradner, {James E.} and Cameron, {Craig E.} and Shadel, {Gerald S.} and Eischen, {Christine M.} and McMahon, {Steven B.}",
note = "Funding Information: We thank Drs. Peter Chumakov, Warren Pear, Trevor Littlewood and Linda Penn for generously providing expression vectors for POLRMT and MYC, and Dr. Martin Eilers for generously providing U2OS MYC/ER cells. The 2'C-methyladenosine compound was a generous gift of Dr. Joy Feng and Gilead Sciences, Inc. In addition, we thank Drs. Gyorgy Hajnoczky, Craig Thompson, Brian Keith, Celeste Simon, Maureen Murphy and Amanda Norvell for helpful discussions. The results shown here are in whole or part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. This work was supported by grants from the NIH: CA090465 and CA141070 (to SBM), F31CA183158 (to ARO), CA148950 (to CME), F31CA165728 (to CMA). GSS is a Joseph A. and Lucille K. Madri Professor of Experimental Pathology and also supported NIH grant AG047632. The Kimmel Cancer Center Flow Cytometry shared resource is supported by Cancer Center Support Grant 5P30CA056036-17.",
year = "2016",
doi = "10.18632/oncotarget.11718",
language = "English (US)",
volume = "7",
pages = "72395--72414",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "45",
}