title: MYC and EGR1 synergize to trigger tumor cell death by controlling NOXA and BIM transcription upon treatment with the proteasome inhibitor bortezomib.
abstract: The c-MYC (MYC afterward) oncogene is well known for driving numerous oncogenic programs. However, MYC can also induce apoptosis and this function of MYC warrants further clarification. We report here that a clinically relevant proteasome inhibitor significantly increases MYC protein levels and that endogenous MYC is necessary for the induction of apoptosis. This kind of MYC-induced cell death is mediated by enhanced expression of the pro-apoptotic BCL2 family members NOXA and BIM. Quantitative promoter-scanning chromatin immunoprecipitations (qChIP) further revealed binding of MYC to the promoters of NOXA and BIM upon proteasome inhibition, correlating with increased transcription. Both promoters are further characterized by the presence of tri-methylated lysine 4 of histone H3, marking active chromatin. We provide evidence that in our apoptosis models cell death occurs independently of p53 or ARF. Furthermore, we demonstrate that recruitment of MYC to the NOXA as well as to the BIM gene promoters depends on MYC's interaction with the zinc finger transcription factor EGR1 and an EGR1-binding site in both promoters. Our study uncovers a novel molecular mechanism by showing that the functional cooperation of MYC with EGR1 is required for bortezomib-induced cell death. This observation may be important for novel therapeutic strategies engaging the inherent pro-death function of MYC.
authors.affiliation: Medizinische Klinik, Technische Universität München, München 81675, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wirth
authors.affiliation: Medizinische Klinik, Technische Universität München, München 81675, Germany.
authors.forename: Natasa
authors.initials: N
authors.lastname: Stojanovic
authors.affiliation: Departments of Medicine and of Microbiology and Immunology, The Research Institute of the McGill University Health Centre, McGill University, Montréal H3A 2B4, Canada.
authors.forename: Jan
authors.initials: J
authors.lastname: Christian
authors.affiliation: Medizinische Klinik, Technische Universität München, München 81675, Germany.
authors.forename: Mariel C
authors.initials: MC
authors.lastname: Paul
authors.affiliation: Molecular and Cellular Oncology/Mainz Screening Center (MSC), University Hospital of Mainz, Mainz 55101, Germany.
authors.forename: Roland H
authors.initials: RH
authors.lastname: Stauber
authors.affiliation: Medizinische Klinik, Technische Universität München, München 81675, Germany.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinik Freiburg, Freiburg 79104, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Häcker
authors.affiliation: Department of Toxicology, University of Mainz Medical Center, Mainz 55131, Germany.
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Krämer
authors.affiliation: Medizinische Klinik, Technische Universität München, München 81675, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.affiliation: Medizinische Klinik, Technische Universität München, München 81675, Germany guenter.schneider@lrz.tum.de.
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D001665:Binding Sites; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D016158:Genes, p53; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D011401:Promoter Regions, Genetic; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001897:Boronic Acids; D051766:Early Growth Response Protein 1; D008565:Membrane Proteins; C408009:Pmaip1 protein, mouse; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D000069286:Bortezomib