DNA/RNA-binding protein KIN17 supports esophageal cancer progression via resolving noncanonical STING activation induced by R-loop
Abstract Targeting the DNA damage response (DDR) exhibits potent efficacy in inducing immune activation and enhancing patient prognosis. However, the benefits of DDR regulation are not universally observed across all patients, owing to the intricate compensatory mechanisms operative in certain cance...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-08-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02344-2 |
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| Summary: | Abstract Targeting the DNA damage response (DDR) exhibits potent efficacy in inducing immune activation and enhancing patient prognosis. However, the benefits of DDR regulation are not universally observed across all patients, owing to the intricate compensatory mechanisms operative in certain cancers. There still exists a gap in the function of activated DDR protein in esophageal squamous cell carcinoma (ESCC). Here, we demonstrate that increased expression of DDR genes contributes to the progression of esophageal squamous cell carcinoma and suppresses the tumor immune microenvironment. Notably, the abundant presence of the DDR protein KIN in ESCC tissues facilitates efficient DNA damage clearance and promotes escape from apoptosis. Depletion of KIN significantly inhibited proliferation and induced DNA damage accumulation in ESCC cells. Mechanistically, KIN functions to support the recruitment of the R-loop regulator DHX9 to R-loop sites, thereby addressing DNA damage associated R-loops. Intriguingly, the depletion of KIN activates the STING pathway via NFκB signaling, which is induced by the accumulation of R-loops, ultimately initiating an innate immune response. Depletion of KIN improved the immune microenvironment and the effect of immune therapy in mouse model. Collectively, our findings identify KIN as a novel R-loop binding protein that facilitates the recruitment of the R-loop resolution complex and suppresses tumor-intrinsic innate immunity. |
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| ISSN: | 2059-3635 |