Journal Article

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

Yu, Yanbao, Zhao, Bao, Cheng, Xiang, Xin, Gang, Wang, Jing, Li, Tianliang, Li, Zihai, Dong, Hong, Lei, Yu L, Gong, Wang, Zhang, Junran, Wen, Haitao, Chen, Jianwen, Black, Jennifer D

2024

Overview

The O -GlcNAc transferase (OGT) is an essential enzyme that mediates protein O -GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O -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 ( 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 Apc gene ( Apc min ). 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 Cgas or Sting from Ogt −/− 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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd
• Subject: Analysis / Animal models / Animals / Antitumor activity / APC gene / Biological response modifiers / Cancer / CD8 antigen / Cell-mediated immunity / Cellular signal transduction / cGAS / Clonal deletion / Colorectal cancer / Colorectal Neoplasms - genetics / Colorectal Neoplasms - immunology / Colorectal Neoplasms - metabolism / Cyclic guanylic acid / Development and progression / Disease Models, Animal / Enzymes / Gene deletion / Genes / 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 - antagonists & inhibitors / Nucleotidyltransferases - genetics / Nucleotidyltransferases - metabolism / O-GlcNAcylation / OGT / Oncology, Experimental / Pathogenesis / Phosphorylation / Post-translational modification / Protein expression / Proteins / Scientific equipment and supplies industry / Signal Transduction / STING / T cells / Transferases / tumor immunity / Tumorigenesis / Tumors