Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through 
mouse knockout studies as a tumor suppressor for the development of colon 
adenocarcinomas. This study investigates the regulation of FXR in the 
development of human colon cancer. We used immunohistochemistry of FXR in normal 
tissue (n = 238), polyps (n = 32), and adenocarcinomas, staged I-IV (n = 43, 39, 
68, and 9), of the colon; RT-quantitative PCR, reverse-phase protein array, and 
Western blot analysis in 15 colon cancer cell lines; NR1H4 promoter methylation 
and mRNA expression in colon cancer samples from The Cancer Genome Atlas; DNA 
methyltransferase inhibition; methyl-DNA immunoprecipitation (MeDIP); bisulfite 
sequencing; and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) 
knockdown assessment to investigate FXR regulation in colon cancer development. 
Immunohistochemistry and quantitative RT-PCR revealed that expression and 
function of FXR was reduced in precancerous lesions and silenced in a majority 
of stage I-IV tumors. FXR expression negatively correlated with 
phosphatidylinositol-4, 5-bisphosphate 3 kinase signaling and the 
epithelial-to-mesenchymal transition. The NR1H4 promoter is methylated in ~12% 
colon cancer The Cancer Genome Atlas samples, and methylation patterns segregate 
with tumor subtypes. Inhibition of DNA methylation and KRAS silencing both 
increased FXR expression. FXR expression is decreased early in human colon 
cancer progression, and both DNA methylation and KRAS signaling may be 
contributing factors to FXR silencing. FXR potentially suppresses 
epithelial-to-mesenchymal transition and other oncogenic signaling cascades, and 
restoration of FXR activity, by blocking silencing mechanisms or increasing 
residual FXR activity, represents promising therapeutic options for the 
treatment of colon cancer.