Nuclear adenomatous polyposis coli elevates STAT1 and reduces CXCL1,2, and 3 expression and inhibits neutrophil recruitment.

Adenomatous polyposis coli (APC) mutations and chronic inflammation can each promote colon cancer. Though both mice and humans with germline APC mutations show reduced tumorigenesis if treated with anti-inflammatory agents, direct links between APC and inflammation remain incomplete. In the current study, we examine a novel role for APC in intestinal inflammation via inhibition of neutrophil-recruiting chemokines CXCL1, 2, and 3. Patients with colorectal adenocarcinoma, the majority of whom would be expected to harbor APC mutations, showed upregulated CXCL1, 2, and 3 expression at early stages of disease. APC induction in cultured human colon cells reduced levels of CXCL1 and CXCL2 proteins and CXCL1, CXCL2, and CXCL3 RNAs and increased expression of signal transducer and activator of transcription 1 (STAT1), a potential negative regulator of CXCL1 transcription. By mining published Chromatin-immunoprecipitation sequencing (ChIP-Seq) data, we found regions of the STAT1 promoter and upstream CpG island as APC-bound. Methylation-specific PCR and bisulfite sequencing each revealed decreased methylation of the STAT1 CpG island upon APC induction. Intestinal tissue explants from mice compromised for nuclear Apc (Apc) secreted more CXCL1 and CXCL2 than wild-type explants. Conditioned media from APC-expressing cells recruited fewer neutrophils in a trans-well migration assay. In vivo, colon and ileal tissues from Apc mice displayed more neutrophils than Apc mice. Experimental evidence from in vitro and in vivo systems validates that nuclear APC can inhibit inflammation by suppressing neutrophil-recruiting chemokines CXCL1, 2, and 3, potentially via epigenetic regulation of STAT1. These findings offer a new target for managing inflammation in inflammatory bowel disease and reveal a new mechanism by which APC loss enables cancer progression.