c-MYC inhibition impairs hypoxia response in glioblastoma multiforme.
The c-MYC oncoprotein is a DNA binding transcription factor that enhances the expression of many active genes. c-MYC transcriptional signatures vary according to the transcriptional program defined in each cell type during differentiation. Little is known on the involvement of c-MYC in regulation of gene expression programs that are induced by extracellular cues such as a changing microenvironment. Here we demonstrate that inhibition of c-MYC in glioblastoma multiforme cells blunts hypoxia-dependent glycolytic reprogramming and mitochondria fragmentation in hypoxia. This happens because c-MYC inhibition alters the cell transcriptional response to hypoxia and finely tunes the expression of a subset of Hypoxia Inducible Factor 1-regulated genes. We also show that genes whose expression in hypoxia is affected by c-MYC inhibition are able to distinguish the Proneural subtype of glioblastoma multiforme, thus potentially providing a molecular signature for this class of tumors that are the least tractable among glioblastomas.
Institute of Cell Biology and Neurobiology, CNR, c/o CERC, 00143 Rome, Italy.
Maria Patrizia
MP
Mongiardi
Nucleic Acids Laboratory, Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR) and Department of Biology and Biotechnologies, Sapienza University, 00185 Rome, Italy.
Mauro
M
Savino
Institute of Cell Biology and Neurobiology, CNR, c/o CERC, 00143 Rome, Italy.
Maria Laura
ML
Falchetti
Nucleic Acids Laboratory, Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR) and Department of Biology and Biotechnologies, Sapienza University, 00185 Rome, Italy.
Barbara
B
Illi
Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.|Fondazione Santa Lucia IRCCS, c/o CERC, 00143 Rome, Italy.
Francesca
F
Bozzo
Institute of Cell Biology and Neurobiology, CNR, c/o CERC, 00143 Rome, Italy.|Fondazione Santa Lucia IRCCS, c/o CERC, 00143 Rome, Italy.
Cristiana
C
Valle
Centre for Molecular Bioinformatics, Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
Manuela
M
Helmer-Citterich
Department of Pharmacy and Biotechnology (FaBiT), University of Bologna Alma Mater, 40126 Bologna, Italy.
Fabrizio
F
Ferrè
Nucleic Acids Laboratory, Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR) and Department of Biology and Biotechnologies, Sapienza University, 00185 Rome, Italy.
Sergio
S
Nasi
Institute of Cell Biology and Neurobiology, CNR, c/o CERC, 00143 Rome, Italy.
Andrea
A
Levi
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment
D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C489427:MYC protein, human; D010446:Peptide Fragments; D016271:Proto-Oncogene Proteins c-myc; C568271:omomyc protein
HIF; c-MYC; glioblastoma; glycolysis; hypoxia