Format

Send to

Choose Destination
Oncogene. 2018 Jul;37(30):4181-4196. doi: 10.1038/s41388-018-0256-6. Epub 2018 May 2.

Identification of a MET-eIF4G1 translational regulation axis that controls HIF-1α levels under hypoxia.

Author information

1
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, 3010, Switzerland.
2
Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, 3008, Switzerland.
3
Department for BioMedical Research, Visceral and Transplantation Surgery, Inselspital, Bern University Hospital, and University of Bern, Bern, 3008, Switzerland.
4
Institute of Pathology, University of Bern, Bern, 3008, Switzerland.
5
Institute of Pathology, Basel University Hospital, Basel, 4031, Switzerland.
6
Global Research & Development, Merck KGaA, Darmstadt, 64293, Germany.
7
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, 3010, Switzerland. yitzhak.zimmer@insel.ch.
8
Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, 3008, Switzerland. yitzhak.zimmer@insel.ch.

Abstract

Poor oxygenation is a common hallmark of solid cancers that strongly associates with aggressive tumor progression and treatment resistance. While a hypoxia-inducible factor 1α (HIF-1α)-associated transcriptional overexpression of the hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) MET has been previously documented, any regulation of the HIF-1α system through MET downstream signaling in hypoxic tumors has not been yet described. By using MET-driven in vitro as well as ex vivo tumor organotypic fresh tissue models we report that MET targeting results in depletion of HIF-1α and its various downstream targets. Mechanistically, we provide evidence that MET regulates HIF-1α levels through a protein translation mechanism that relies on phosphorylation modulation of the eukaryotic initiation factor 4G1 (eIF4G1) on serine 1232 (Ser-1232). Targeted phosphoproteomics data demonstrate a significant drop in eIF4G1 Ser-1232 phosphorylation following MET targeting, which is linked to an increased affinity between eIF4G1 and eIF4E. Since phosphorylation of eIF4G1 on Ser-1232 is largely mediated through mitogen-activated protein kinase (MAPK), we show that expression of a constitutively active K-RAS variant is sufficient to abrogate the inhibitory effect of MET targeting on the HIF-1α pathway with subsequent resistance of tumor cells to MET targeting under hypoxic conditions. Analysis of The Cancer Genome Atlas data demonstrates frequent co-expression of MET, HIF-1α and eIF4G1 in various solid tumors and its impact on disease-free survival of non-small cell lung cancer patients. Clinical relevance of the MET-eIF4G1-HIF-1α pathway is further supported by a co-occurrence of their expression in common tumor regions of individual lung cancer patients.

PMID:
29717265
DOI:
10.1038/s41388-018-0256-6
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center