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., Bradner, J. E., Cameron, C. E., Shadel, G. S., Eischen, C. M., McMahon, S. B. (November 2016) Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer. Oncotarget, 7 (45). pp. 72395-72414. ISSN 1949-2553 (Electronic)1949-2553 (Linking)
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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Myc mitochondria mitochondrial gene expression synthetic lethality tigecycline |
| Subjects: | diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression organs, tissues, organelles, cell types and functions > organelles, types and functions > mitochondria |
| CSHL Authors: | |
| Communities: | CSHL labs > Vakoc lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: | Matt Covey |
| Date: | 8 November 2016 |
| Date Deposited: | 08 Sep 2016 20:49 |
| Last Modified: | 05 Nov 2020 16:54 |
| PMCID: | PMC5340124 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33428 |
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