Inhibition of O-GlcNAc transferase activates cGAS-STING pathway

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 mouse
tumor models and a genetic mice colorectal cancer (CRC) model induced by
mutation of the Apc gene (Apcmin). Pharmacological inhibition or genetic
deletion of OGT induced 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
the cGAS-STING pathway as an important tumor cell-intrinsic mechanism to
repress antitumor immunity.