Maintenance of p-eIF2α levels by the eIF2B complex is vital for colorectal cancer
Protein synthesis is an essential process, deregulated in multiple tumor types showing differential dependence on translation factors compared to untransformed tissue. We show that colorectal cancer (CRC) with loss-of-function mutation in the APC tumor suppressor depends on an oncogenic translation program regulated by the ability to sense phosphorylated eIF2α (p-eIF2α). Despite increased protein synthesis rates following APC loss, eIF2α phosphorylation, typically associated with translation inhibition, is enhanced in CRC. Elevated p-eIF2α, and its proper sensing by the decameric eIF2B complex, are essential to balance translation. Knockdown or mutation of eIF2Bα and eIF2Bδ, two eIF2B subunits responsible for sensing p-eIF2α, impairs CRC viability, demonstrating that the eIF2B/p-eIF2α nexus is vital for CRC. Specifically, the decameric eIF2B linked by two eIF2Bα subunits is critical for translating growth-promoting mRNAs which are induced upon APC loss. Depletion of eIF2Bα in APC-deficient murine and patient-derived organoids establishes a therapeutic window, validating eIF2Bα as a target for clinical intervention. In conclusion, we demonstrate how the expression of the oncogenic signature in CRC is crucially controlled at the translational level.
Authors
- Chiara Giacomelli (ORCID: https://orcid.org/0000-0003-1466-1371)
- Rene-Filip Jackstadt
- Stephan A. Hahn (ORCID: https://orcid.org/0000-0003-0855-9741)
- Christina Schülein‐Völk
- Mathias Diebold (ORCID: https://orcid.org/0000-0002-7595-3901)
- Martin Bushell (ORCID: https://orcid.org/0000-0001-9938-2691)
- Christoph Otto (ORCID: https://orcid.org/0000-0001-7004-1594)
- Katja Maurus (ORCID: https://orcid.org/0000-0002-3093-3114)
- Nicolas Schlegel (ORCID: https://orcid.org/0000-0001-5705-3945)
- Andreas Rosenwald (ORCID: https://orcid.org/0000-0001-7282-8374)
- Peter Gallant (ORCID: https://orcid.org/0000-0002-8270-5738)
- Nikolai Schleußner (ORCID: https://orcid.org/0009-0001-3549-5600)
- Anne Hendricks
- Martin Eilers (ORCID: https://orcid.org/0000-0002-0376-6533)
- Josep Biayna (ORCID: https://orcid.org/0000-0002-0842-7530)
- Hanna Deinlein
- Armin Wiegering (ORCID: https://orcid.org/0000-0001-7777-0909)
- Stefanie Schmidt (ORCID: https://orcid.org/0000-0003-2053-0909)
- Elmar Wolf (ORCID: https://orcid.org/0000-0002-5299-6335)
- Christoph‐Thomas Germer
- Carolin Kastner
- Ivana Paskov Škapik
- Leon Olimski
Institutions
- Goethe University Frankfurt (DE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University of Würzburg (DE)
- Frankfurt Institute for Advanced Studies (DE)
- University Hospital Heidelberg (DE)
- Hochschule für Angewandte Wissenschaften Kiel (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Comprehensive Cancer Center Mainfranken (DE)
- Universitätsklinikum Würzburg (DE)
- University Hospital Frankfurt (DE)
- Cancer Research UK Scotland Institute (GB)
- DKFZ-ZMBH Alliance (DE)
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE)
- Clinical Research Center Kiel (DE)
- University of Glasgow (GB)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-02-27
- DOI
- https://doi.org/10.1038/s44318-025-00381-9
- Citations
- 3
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Wilhelm Sander-Stiftung
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe