c-MYC inhibition impairs hypoxia response in glioblastoma multiforme

• Published in: Oncotarget Vol. 7; no. 22; pp. 33257 - 33271
• Main Authors: Mongiardi, Maria Patrizia, Savino, Mauro, Falchetti, Maria Laura, Illi, Barbara, Bozzo, Francesca, Valle, Cristiana, Helmer-Citterich, Manuela, Ferrè, Fabrizio, Nasi, Sergio, Levi, Andrea
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 31.05.2016
• Subjects: Antineoplastic Agents - pharmacology; Binding Sites; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Energy Metabolism - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glycolysis - drug effects; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Peptide Fragments - pharmacology; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - metabolism; Proto-Oncogene Proteins c-myc - pharmacology; Research Paper; Signal Transduction - drug effects; Time Factors; Transcription, Genetic - drug effects; Tumor Hypoxia; Tumor Microenvironment; hypoxia; glioblastoma; HIF; c-MYC; glycolysis
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8921

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.