Inhibition of O -GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway

• Published in: eLife 2024-10, Vol.13
• Main Authors: Chen, Jianwen, Zhao, Bao, Dong, Hong, Li, Tianliang, Cheng, Xiang, Gong, Wang, Wang, Jing, Zhang, Junran, Xin, Gang, Yu, Yanbao, Lei, Yu L, Black, Jennifer D, Li, Zihai, Wen, Haitao
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antitumor activity; APC gene; Cancer; CD8 antigen; Cell-mediated immunity; Cellular signal transduction; cGAS; Clonal deletion; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - metabolism; Development and progression; Disease Models, Animal; Gene deletion; Genetic aspects; Genomic instability; Health aspects; Humans; Immunity; Immunity (Disease); Interferon; Interferon Type I - metabolism; Kinases; Lymphocytes T; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metastasis; Mice; Mice, Inbred C57BL; Mice, Knockout; N-Acetylglucosaminyltransferases - genetics; N-Acetylglucosaminyltransferases - metabolism; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; O-GlcNAcylation; OGT; Oncology, Experimental; Pathogenesis; Phosphorylation; Post-translational modification; Protein expression; Proteins; Signal Transduction; STING; Transferases; tumor immunity; Tumorigenesis
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.94849

The -GlcNAc transferase (OGT) is an essential enzyme that mediates protein -GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and -GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent mice by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT ( ) caused a marked reduction in tumor growth in both syngeneic mice tumor models and a genetic mice colorectal cancer (CRC) model induced by mutation of the gene ( ). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of or from cancer cells restored tumor growth, and this correlated with impaired CD8 T-cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor-cell-intrinsic mechanism to repress antitumor immunity.