%0 Journal Article
%A Škapik, Ivana Paskov
%A Giacomelli, Chiara
%A Hahn, Sarah
%A Deinlein, Hanna
%A Gallant, Peter
%A Diebold, Mathias
%A Biayna, Josep
%A Hendricks, Anne
%A Olimski, Leon
%A Otto, Christoph
%A Kastner, Carolin
%A Wolf, Elmar
%A Schülein-Völk, Christina
%A Maurus, Katja
%A Rosenwald, Andreas
%A Schleussner, Nikolai
%A Jackstadt, Rene-Filip
%A Schlegel, Nicolas
%A Germer, Christoph-Thomas
%A Bushell, Martin
%A Eilers, Martin
%A Schmidt, Stefanie
%A Wiegering, Armin
%T Maintenance of p-eIF2α levels by the eIF2B complex is vital for colorectal cancer.
%J The EMBO journal
%V 44
%@ 0261-4189
%C [London]
%I Nature Publishing Group UK
%M DKFZ-2025-00454
%P 2075 - 2105
%D 2025
%Z ZMBH Alliance / EMBO J, (2025), 44: 2075 - 2105
%X 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.
%K APC (Other)
%K Colorectal Cancer (Other)
%K Translation (Other)
%K eIF2B (Other)
%K eIF2α (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40016419
%R DOI:10.1038/s44318-025-00381-9
%U https://inrepo02.dkfz.de/record/299495