Loss of the translational repressor 4E-BP1 promotes skin carcinogenesis.

INTRODUCTION: Skin squamous cell carcinoma (SCC) arises from dysregulated epidermal homeostasis characterized by aberrant keratinocyte proliferation and pathological angiogenesis. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) functions as a critical suppressor of cap-dependent translation by interacting with eIF4E, thereby constraining protein synthesis and cell growth. However, its role in SCC remains elusive. METHODS: To address the role of 4E-BP1 function in SCC pathogenesis, we employed a two-stage chemical carcinogenesis model in 4E-BP1-deficient mice. RESULTS: 4E-BP1-deficient mice exhibited a significantly increased papilloma burden compared to wild-type controls, accompanied by enhanced keratinocyte proliferation and augmented tumor vascularization. Analysis of human SCC specimens revealed elevated 4E-BP1 phosphorylation together with increased proliferative and angiogenic markers and activation of the mTOR signaling pathway, mirroring molecular features observed in 4E-BP1-deficient tumors. DISCUSSION: Collectively, these findings establish 4E-BP1 as a tumor suppressor in skin carcinogenesis that constrains both proliferative and angiogenic processes, underscoring the contribution of dysregulated translation to SCC development.