Farnesoid X receptor antagonizes Wnt/β-catenin signaling in colorectal tumorigenesis

Farnesoid X receptor (FXR, encoded by NR1H4), a critical regulator of bile acid homeostasis, is widely implicated in human tumorigenesis. However, the functional role of FXR in colorectal cancer (CRC) and the precise molecular mechanism remain unclear. In this study, we demonstrated that FXR expression was downregulated in colon cancer tissues and decreased expression of FXR predicted a poor prognosis. Knockdown of FXR promoted colon cancer cell growth and invasion in vitro, and facilitated xenograft tumor formation and distant metastasis in vivo, whereas ectopic expression of FXR had the reserved change. Mechanistic studies indicated that FXR exerted its tumor suppressor functions by antagonizing Wnt/beta-catenin signaling. Furthermore, we identified an FXR/beta-catenin interaction in colon cancer cells. The FXR/beta-catenin interaction impaired beta-catenin/TCF4 complex formation. In addition, our study suggested a reciprocal relationship between FXR and beta-catenin, since loss of beta-catenin increased the transcriptional activation of SHP by FXR. Altogether, these data indicated that FXR functions a tumor-suppressor role in CRC by antagonizing Wnt/beta-catenin signaling.