MYC is downregulated by a mitochondrial checkpoint mechanism

Xiaonan Zhang; Arjan Mofers; Per Hydbring; Maria Hägg Olofsson; Jing Guo; Stig Linder; Padraig D’Arcy

doi:10.18632/oncotarget.21653

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Research Papers:

MYC is downregulated by a mitochondrial checkpoint mechanism

Xiaonan Zhang, Arjan Mofers, Per Hydbring, Maria Hägg Olofsson, Jing Guo, Stig Linder _ and Padraig D’Arcy

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Oncotarget. 2017; 8:90225-90237. https://doi.org/10.18632/oncotarget.21653

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Abstract

Xiaonan Zhang1, Arjan Mofers2, Per Hydbring1, Maria Hägg Olofsson1, Jing Guo3,4, Stig Linder1,2 and Padraig D'Arcy2

1Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden

2Department of Medical and Health Sciences, Linköping University, SE-581 83 Linköping, Sweden

3Department of Medical Biochemistry and Biophysics (MBB), Karolinska Institute, SE-171 77 Stockholm, Sweden

4Cardiovascular and Metabolic Disorders Program, Duke-NUS (National University of Singapore) Medical School, 16957 Singapore, Singapore

Correspondence to:

Stig Linder, email: [email protected]

Padraig D’Arcy, email: [email protected]

Keywords: mitochondria, MYC, CRD-BP, let-7/miR-34a, cancer

Received: July 15, 2017 Accepted: August 25, 2017 Published: October 06, 2017

ABSTRACT

The MYC proto-oncogene serves as a rheostat coupling mitogenic signaling with the activation of genes regulating growth, metabolism and mitochondrial biogenesis. Here we describe a novel link between mitochondria and MYC levels. Perturbation of mitochondrial function using a number of conventional and novel inhibitors resulted in the decreased expression of MYC mRNA. This decrease in MYC mRNA occurred concomitantly with an increase in the levels of tumor-suppressive miRNAs such as members of the let-7 family and miR-34a-5p. Knockdown of let-7 family or miR-34a-5p could partially restore MYC levels following mitochondria damage. We also identified let-7-dependent downregulation of the MYC mRNA chaperone, CRD-BP (coding region determinant-binding protein) as an additional control following mitochondria damage. Our data demonstrates the existence of a homeostasis mechanism whereby mitochondrial function controls MYC expression.

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Research Papers:

MYC is downregulated by a mitochondrial checkpoint mechanism

Abstract