TY  - JOUR
AU  - Škapik, Ivana Paskov
AU  - Giacomelli, Chiara
AU  - Hahn, Sarah
AU  - Deinlein, Hanna
AU  - Gallant, Peter
AU  - Diebold, Mathias
AU  - Biayna, Josep
AU  - Hendricks, Anne
AU  - Olimski, Leon
AU  - Otto, Christoph
AU  - Kastner, Carolin
AU  - Wolf, Elmar
AU  - Schülein-Völk, Christina
AU  - Maurus, Katja
AU  - Rosenwald, Andreas
AU  - Schleussner, Nikolai
AU  - Jackstadt, Rene-Filip
AU  - Schlegel, Nicolas
AU  - Germer, Christoph-Thomas
AU  - Bushell, Martin
AU  - Eilers, Martin
AU  - Schmidt, Stefanie
AU  - Wiegering, Armin
TI  - Maintenance of p-eIF2α levels by the eIF2B complex is vital for colorectal cancer.
JO  - The EMBO journal
VL  - 44
SN  - 0261-4189
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2025-00454
SP  - 2075 - 2105
PY  - 2025
N1  - ZMBH Alliance / EMBO J, (2025), 44: 2075 - 2105
AB  - 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.
KW  - APC (Other)
KW  - Colorectal Cancer (Other)
KW  - Translation (Other)
KW  - eIF2B (Other)
KW  - eIF2α (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40016419
DO  - DOI:DOI:10.1038/s44318-025-00381-9
UR  - https://inrepo02.dkfz.de/record/299495
ER  -