c-MYC inhibition impairs hypoxia response in glioblastoma multiforme

Maria Patrizia Mongiardi; Mauro Savino; Maria Laura Falchetti; Barbara Illi; Francesca Bozzo; Cristiana Valle; Manuela Helmer-Citterich; Fabrizio Ferrè; Sergio Nasi; Andrea Levi

doi:10.18632/oncotarget.8921

c-MYC inhibition impairs hypoxia response in glioblastoma multiforme

Oncotarget. 2016 May 31;7(22):33257-71. doi: 10.18632/oncotarget.8921.

Authors

Affiliations

¹ Institute of Cell Biology and Neurobiology, CNR, c/o CERC, 00143 Rome, Italy.
² 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.
³ Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
⁴ Fondazione Santa Lucia IRCCS, c/o CERC, 00143 Rome, Italy.
⁵ Centre for Molecular Bioinformatics, Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
⁶ Department of Pharmacy and Biotechnology (FaBiT), University of Bologna Alma Mater, 40126 Bologna, Italy.

Abstract

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.

Keywords: HIF; c-MYC; glioblastoma; glycolysis; hypoxia.

MeSH terms

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*
Signal Transduction / drug effects
Time Factors
Transcription, Genetic / drug effects
Tumor Hypoxia*
Tumor Microenvironment*

Substances

Antineoplastic Agents
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
MYC protein, human
Peptide Fragments
Proto-Oncogene Proteins c-myc
omomyc protein