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Oncogene

Oncogene

IF: 7.3
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REPS2 attenuates cancer stemness through inhibiting Wnt signaling by autophagy mediated degradation of β-catenin

Published:13 June 2025 DOI: 10.1038/s41388-025-03469-y PMID: 40514427
Lu Liu, Shuzhen Chen, Yuxi Lei, Zejian Lin, Rulan Zhou, Guandi Zeng, Zongyao Zheng, Wanting Liu, Qian Zhou, Liang Chen

Abstract

Tumor suppressor genes (TSGs) that regulate the stemness of lung cancer cells remain to be determined. We conducted a genome-wide CRISPR/Cas9-mediated screening and identified REPS2 as a potent TSG that negatively regulates the stemness of lung cancer cells. Its tumor suppressive function was confirmed both in vitro and in vivo. Mechanistically, P62 interacts simultaneously with both β-catenin and REPS2, leading to autophagy-lysosome-mediated degradation of β-catenin and attenuation of Wnt signaling. A β-catenin inhibitor synergizes with inhibitors for driver mutants to induce immunogenic cell death, which could be exploited for enhancing efficacy of tumor immunotherapy.

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