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

Oncogene volume 37, pages 4181–4196 (2018)Cite this article

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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.

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Acknowledgements

We cordially thank Dr. Nicola Zamboni (ETH Zürich, Switzerland) for his help with metabolomics measurements and data analysis.

Funding

This work has been supported by Stiftung für klinisch-experimentelle Tumorforschung (grant to YZ) and by Stiftung zur Krebsbekämpfung (grant Nr.374/2016 to MM). YZ received a drug donation from Merck / EMD Serono. Merck / EMD Serono has reviewed the publication, and the views and opinions described in the publication do not necessarily reflect those of Merck.

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Authors and Affiliations

  1. Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, 3010, Switzerland

    Astrid A. Glück, Eleonora Orlando, Dominic Leiser, Michaela Poliaková, Lluís Nisa, Aurélie Quintin, Daniel M. Aebersold, Michaela Medová & Yitzhak Zimmer

  2. Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, 3008, Switzerland

    Astrid A. Glück, Eleonora Orlando, Michaela Poliaková, Lluís Nisa, Aurélie Quintin, Daniel M. Aebersold, Michaela Medová & Yitzhak Zimmer

  3. Department for BioMedical Research, Visceral and Transplantation Surgery, Inselspital, Bern University Hospital, and University of Bern, Bern, 3008, Switzerland

    Jacopo Gavini & Deborah M. Stroka

  4. Institute of Pathology, University of Bern, Bern, 3008, Switzerland

    Sabina Berezowska

  5. Institute of Pathology, Basel University Hospital, Basel, 4031, Switzerland

    Lukas Bubendorf

  6. Global Research & Development, Merck KGaA, Darmstadt, 64293, Germany

    Andree Blaukat

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AB is listed as a co-inventor on all patents related to Merck’s c-Met inhibitor referred to in this manuscript. The remaining authors declare that they have no conflict of interest.

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Glück, A.A., Orlando, E., Leiser, D. et al. Identification of a MET-eIF4G1 translational regulation axis that controls HIF-1α levels under hypoxia. Oncogene 37, 4181–4196 (2018). https://doi.org/10.1038/s41388-018-0256-6

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