ArticleInternational journal of biological sciences2026
O-GlcNAcylation stabilizes RSK4 by antagonizing GSK3β-mediated phosphorylation to enhance radioresistance in esophageal squamous cell carcinoma.
Article in International journal of biological sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- A patent perspective of RSK inhibitors to treat cancer (2020-present).Expert opinion on therapeutic patents · 2026Review
- O-GlcNAcylation at the tumor-immune interface: a metabolic post-translational code driving immune evasion and therapy resistance in cancer.Frontiers in immunology · 2026Review
Corrections and comments
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Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignancy characterized by significant radioresistance and poor prognosis. We previously reported that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting cancer stem cell (CSC) properties and radioresistance in ESCC. This study focuses on the regulation of post-translational modifications (PTMs) of RSK4 and their effects on CSC properties and radioresistance. We demonstrate that RSK4 stability and activity are tightly regulated by phosphorylation and O-GlcNAcylation. GSK3β phosphorylates RSK4 at Thr402/Ser406, promoting its degradation via the FBXW7-dependent proteasomal pathway. Additionally, O-GlcNAcylation of RSK4 at Thr405 by OGT inhibits GSK3β-mediated phosphorylation, stabilizing RSK4 and enhancing CSC properties and radioresistance. This antagonistic relationship between phosphorylation and O-GlcNAcylation highlights a novel regulatory mechanism of RSK4 in ESCC. Moreover, targeting RSK4 O-GlcNAcylation with OSMI-4 destabilizes RSK4 and sensitizes ESCC to radiotherapy in both patient-derived xenograft and organoid models. Collectively, this study provides critical insights into the molecular mechanisms underlying ESCC radioresistance and identifies RSK4 O-GlcNAcylation as a potential therapeutic target to improve radiotherapy efficacy and overcome treatment resistance.
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