Journal Article

DKFZ-2025-00454

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Maintenance of p-eIF2α levels by the eIF2B complex is vital for colorectal cancer.

Škapik, I. P. ; Giacomelli, C. ; Hahn, S. ; Deinlein, H. ; Gallant, P. ; Diebold, M. ; Biayna, J. ; Hendricks, A. ; Olimski, L. ; Otto, C. ; Kastner, C. ; Wolf, E. ; Schülein-Völk, C. ; Maurus, K. ; Rosenwald, A. ; Schleussner, N.DKFZ* ; Jackstadt, R.-F.DKFZ* ; Schlegel, N. ; Germer, C.-T. ; Bushell, M. ; Eilers, M. ; Schmidt, S. ; Wiegering, A.

2025
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi: DOI:10.1038/s44318-025-00381-9   doi:DOI:10.1038/s44318-025-00381-9

Abstract: 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.

Keyword(s): APC ; Colorectal Cancer ; Translation ; eIF2B ; eIF2α

Note: ZMBH Alliance / EMBO J, (2025), 44: 2075 - 2105

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Contributing Institute(s):

1. NWG Tumorprogression und Metastasierung (A013)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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