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

Glück, Astrid Andreina; Orlando, Eleonora; Leiser, Dominic; Poliakova, Michaela; Nisa Hernández, Lluís; Quintin, Aurelie; Gavini, Jacopo; Keogh-Stroka, Deborah M.; Berezowska, Sabina; Bubendorf, Lukas; Blaukat, Andree; Aebersold, Daniel; Medova, Michaela; Zimmer, Yitzhak (2018). Identification of a MET-eIF4G1 translational regulation axis that controls HIF-1α levels under hypoxia. Oncogene, 37(30), pp. 4181-4196. Nature Publishing Group 10.1038/s41388-018-0256-6

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine

UniBE Contributor:

Glück, Astrid Andreina; Orlando, Eleonora; Leiser, Dominic; Poliakova, Michaela; Nisa Hernández, Lluís; Quintin, Aurelie; Gavini, Jacopo; Keogh-Stroka, Deborah M.; Berezowska, Sabina Anna; Aebersold, Daniel; Medova, Michaela and Zimmer, Yitzhak

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0950-9232

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

22 Jun 2018 08:37

Last Modified:

23 Aug 2018 08:56

Publisher DOI:

10.1038/s41388-018-0256-6

PubMed ID:

29717265

BORIS DOI:

10.7892/boris.117241

URI:

https://boris.unibe.ch/id/eprint/117241

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