Control of the Human Osteopontin Promoter by ERRα in Colorectal Cancer

Colorectal cancer is the second leading cause of death from cancer. Osteopontin (OPN) is a component of tumor extracellular matrix identified as a key marker of cancer progression. The estrogen-related receptor a (ERR) has been implicated in endocrine-related cancer development and progression, possibly through modulation of cellular energy metabolism. Previous reports that ERR alpha regulates OPN expression in bone prompted us to investigate whether ERR alpha controls OPN expression in human colorectal cancer. Using a tissue microarray containing 83 tumor-normal tissue pairs of colorectal cancer samples, we found that tumor epithelial cells displayed higher staining for ERR alpha than normal mucosa, in correlation with elevated OPN expression. In addition, knocking down endogenous ERR alpha Led to reduced OPN expression in HT29 colon cancer cells. Promoter analysis, inhibition of ERR alpha activity, and expression and mutation of potential ERRa response elements in the proximal promoter of human OPN showed that ERR alpha and its obligate co-activator, peroxisome proliferator-activated receptor gamma co-activator-1 alpha, positively control human OPN promoter activity. Furthermore, chromatin immunoprecipitation experiments confirmed in vivo occupancy of the OPN promoter by ERR alpha in HT29 cells, suggesting that OPN is a direct target of ERR alpha in colorectal cancer. These findings suggest an additional mechanism by which ERR alpha participates in the development and progression of colorectal cancer, further supporting the relevance of targeting ERR alpha with antagonists as anticancer agents.