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.
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Amanda R
authors: AR
authors: Oran
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Clare M
authors: CM
authors: Adams
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Xiao-Yong
authors: XY
authors: Zhang
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Victoria J
authors: VJ
authors: Gennaro
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Harla K
authors: HK
authors: Pfeiffer
authors: Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, PA, USA.
authors: Hestia S
authors: HS
authors: Mellert
authors: Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: Hans E
authors: HE
authors: Seidel
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Kirsten
authors: K
authors: Mascioli
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Jordan
authors: J
authors: Kaplan
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Mahmoud R
authors: MR
authors: Gaballa
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.|Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY, USA.
authors: Chen
authors: C
authors: Shen
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Isidore
authors: I
authors: Rigoutsos
authors: Department of Biochemistry, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Michael P
authors: MP
authors: King
authors: Genetics and Genome Sciences, University of Connecticut Health, Farmington, CT, USA.
authors: Justin L
authors: JL
authors: Cotney
authors: Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
authors: Jamie J
authors: JJ
authors: Arnold
authors: Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
authors: Suresh D
authors: SD
authors: Sharma
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Ubaldo E
authors: UE
authors: Martinez-Outschoorn
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors: Christopher R
authors: CR
authors: Vakoc
authors: Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: Lewis A
authors: LA
authors: Chodosh
authors: Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: James E
authors: JE
authors: Thompson
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA,USA.
authors: James E
authors: JE
authors: Bradner
authors: Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
authors: Craig E
authors: CE
authors: Cameron
authors: Department of Pathology, Yale School of Medicine, New Haven, CT, USA.|Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
authors: Gerald S
authors: GS
authors: Shadel
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Christine M
authors: CM
authors: Eischen
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Steven B
authors: SB
authors: McMahon
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D012321:DNA-Directed RNA Polymerases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D050259:Genes, Mitochondrial; D016259:Genes, myc; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D012321:DNA-Directed RNA Polymerases; C519567:POLRMT protein, human
keywords: MYC; mitochondria; mitochondrial gene expression; synthetic lethality; tigecycline