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cGAS suppresses hepatocellular carcinoma independent of its cGAMP synthase activity

Abstract

Cyclic GMP–AMP synthase (cGAS) is a key innate immune sensor that recognizes cytosolic DNA to induce immune responses against invading pathogens. The role of cGAS is conventionally recognized as a nucleotidyltransferase to catalyze the synthesis of cGAMP upon recognition of cytosolic DNA, which leads to the activation of STING and production of type I/III interferon to fight against the pathogen. However, given that hepatocytes are lack of functional STING expression, it is intriguing to define the role of cGAS in hepatocellular carcinoma (HCC), the liver parenchymal cells derived malignancy. In this study, we revealed that cGAS was significantly downregulated in clinical HCC tissues, and its dysregulation contributed to the progression of HCC. We further identified cGAS as an immune tyrosine inhibitory motif (ITIM) containing protein, and demonstrated that cGAS inhibited the progression of HCC and increased the response of HCC to sorafenib treatment by suppressing PI3K/AKT/mTORC1 pathway in cellular and animal models. Mechanistically, cGAS recruits SH2-containing tyrosine phosphatase 1 (SHP1) via ITIM, and dephosphorylates p85 in phosphatidylinositol 3-kinase (PI3K), which leads to the suppression of AKT-mTORC1 pathway. Thus, cGAS is identified as a novel tumor suppressor in HCC via its function independent of its conventional role as cGAMP synthase, which indicates a novel therapeutic strategy for advanced HCC by modulating cGAS signaling.

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Fig. 1: Loss of cGAS expression was correlated with poor prognosis in HCC patients.
Fig. 2: cGAS suppressed the tumorigenesis of HCC cells.
Fig. 3: cGAS inhibited the AKT-mTORC1 pathway in HCC cells.
Fig. 4: cGAS recruited and interacted with SHP1 in HCC cells.
Fig. 5: cGAS-SHP1 dephosphorylated p85 and suppressed PI3K–AKT pathway.
Fig. 6: cGAS inhibited HCC via the SHP1–p85 axis independent of its nucleotidyltransferase activity.
Fig. 7: cGAS reversed the resistance to sorafenib treatment in HCC by inhibiting AKT pathway.
Fig. 8: Schematic working model.

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Data availability

The datasets used during the current study are available from the corresponding authors (hanlihui@sdu.edu.cn) on reasonable request. Raw western blots are available in the Supplementary file.

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Acknowledgements

The authors thank Dr. Q Sun (Sun Yat-sen University, China) for SHP1 plasmid, Dr. X Yang (Shandong University, China) for assisting with structural and sequences analysis of cGAS, Dr. D Yuan (Shandong University, China) and Dr. H Wen (Ohio State University, USA) for constructive discussion about this work. The authors thank the Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work.

Funding

This study is funded by National Natural Science Foundation of China (Nos. 81972275, 82171748, and 32200709); Distinguished Professor of Taishan Scholars (No. tstp20221109), Shandong Provincial Natural Science Foundation Joint Fund (No. ZR202306180008), and the Major Innovation Project of Shandong Province (No. 2021GXGC011305).

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DM and LH designed this study, analyzed the data, and wrote the manuscript. DM performed most of the experiments. MY assisted with the cell experiment. CS assisted with the confocal microscopy capture. XC, HC, and SL assisted with the animal experiments and related assay. XG assisted with the animal experiments. QW, WJ, XL, TL, and YZ assisted with the experiments and provided technical help. All authors read the final version of the manuscript and approved the submission.

Corresponding author

Correspondence to Lihui Han.

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Ma, D., Yang, M., Sun, C. et al. cGAS suppresses hepatocellular carcinoma independent of its cGAMP synthase activity. Cell Death Differ 31, 722–737 (2024). https://doi.org/10.1038/s41418-024-01291-9

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