Farnesoid X receptor represses matrix metalloproteinase 7 expression, revealing this regulatory axis as a promising therapeutic target in colon cancer

• Published in: The Journal of biological chemistry 2019-05, Vol.294 (21), p.8529-8542
• Main Authors: Peng, Zhongsheng, Chen, Jiayan, Drachenberg, Cinthia B., Raufman, Jean-Pierre, Xie, Guofeng
• Format: Article
• Language: English
• Subjects: Animals; bile acid; Caco-2 Cells; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; colorectal cancer; FXR response element; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; gene promoter; Gene Regulation; HCT116 Cells; HT29 Cells; Humans; matrix metalloproteinase (MMP); Matrix Metalloproteinase 7 - biosynthesis; Matrix Metalloproteinase 7 - genetics; Mice; Mice, Knockout; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; nuclear receptor; oncogenesis; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Response Elements; transcriptional regulation; transcriptional repression; tumor suppressor gene
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA118.004361

The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of bile acid–activated transcription factors and an important regulator of cell proliferation, apoptosis, and Wnt signaling. Down-regulated expression of FXR plays an important role in some malignancies such as colon cancer, and in rodent models of intestinal neoplasia, FXR knockout increases the size and number of colon tumors. These previous observations implicate FXR as a tumor suppressor, but the underlying molecular mechanisms are unclear. Employing complementary experimental approaches and using human colon cancer specimens, human and murine colon cancer cell lines, and FXR transgenic mice, here we identified an additional, potentially important role for FXR. We observed an inverse relationship between the expression of FXR and matrix metalloproteinase-7 (MMP7), a collagenase and signaling molecule consistently associated with colon cancer progression. We noted that FXR gene ablation increases MMP7 expression. Consistent with this finding, FXR overexpression and a dominant-negative FXR mutation reduced and augmented, respectively, MMP7 expression. Of note, MMP7 was the only MMP gene family member whose expression was down-regulated after FXR activation. FXR-mediated regulation of MMP7 transcription did not require heterodimerization with the retinoid X receptor (RXR), indicating that FXR represses MMP7 expression independently of RXR. Last, we uncovered that FXR suppresses MMP7 transcription by binding to a negative FXR-responsive element in the 5′ MMP7 promoter, an event that inhibited colon cancer cell proliferation and invasion. These findings identify the FXR-MMP7 axis as a potential therapeutic target for managing colon cancer.