Oncotarget

Research Papers:

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 and Andrea Levi

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Oncotarget. 2016; 7:33257-33271. https://doi.org/10.18632/oncotarget.8921

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Abstract

Maria Patrizia Mongiardi1,*, Mauro Savino2,*, Maria Laura Falchetti1, Barbara Illi2, Francesca Bozzo3,4, Cristiana Valle1,4, Manuela Helmer-Citterich5, Fabrizio Ferrè6, Sergio Nasi2,**, Andrea Levi1,**

1Institute of Cell Biology and Neurobiology, CNR, c/o CERC, 00143 Rome, Italy

2Nucleic Acids Laboratory, Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR) and Department of Biology and Biotechnologies, Sapienza University, 00185 Rome, Italy

3Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy

4Fondazione Santa Lucia IRCCS, c/o CERC, 00143 Rome, Italy

5Centre for Molecular Bioinformatics, Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy

6Department of Pharmacy and Biotechnology (FaBiT), University of Bologna Alma Mater, 40126 Bologna, Italy

*These two authors contributed equally to this work

**co-senior authors

Correspondence to:

Maria Patrizia Mongiardi, e-mail: mariapatrizia.mongiardi@ibcn.cnr.it

Andrea Levi, e-mail: andrea.levi@cnr.it

Keywords: HIF, c-MYC, hypoxia, glycolysis, glioblastoma

Received: January 7, 2016    Accepted: March 31, 2016    Published: April 22, 2016

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.


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