An Upstream RUNX3 Enhancer, eR3 (-18m/-28h), Regulates the Development of Gut-Associated Anti-Tumorigenic CD8⁺CD103⁺...

The RUNX3 gene is frequently involved in a variety of cancers and immunological diseases. Despite such widespread association with human diseases, the transcriptional regulation of RUNX3 remains elusive. Here we report the identification of an enhancer for Runx3, eR3(-18m/-28h), by employing a combination of in silico prediction and in vivo verification using zebrafish and mouse models. eR3 is active in CD8⁺CD103 (integrin α_E)⁺ cytotoxic T lymphocytes (CTLs) that reside in the intestinal epithelium via their interaction with the CD103 ligand, E-cadherin, on epithelial cells. Removal of eR3(-18m) specifically in CD8 T cells compromised the suppression of tumorigenesis in murine cancer models. In humans, single nucleotide polymorphisms (SNPs) in eR3(-28h) were overrepresented and were associated with weakened CTL activity in colorectal cancer patients. Together, our results indicate that eR3 plays a role in immune surveillance against gut-associated tumors by upregulating RUNX3 expression in specific CTLs.