ERR metabolic nuclear receptor controls growth of colon cancer cells

The estrogen-related receptor alpha (ERR) is a nuclear receptor that acts primarily as a regulator of metabolic processes, particularly in tissues subjected to high-energy demand. In addition to its control of energy metabolism and mitochondrial biogenesis, ERR has recently been associated with cancer progression. Notably, increased expression of ERR has been shown in several cancerous tissues, including breast, ovary and colon. However, additional studies are required to gain insight into the action of ERR in cancer biology, particularly in non-endocrine-related cancers. Therefore, using a short hairpin RNA-mediated approach, we investigated whether ERR is required for the rapid growth of colon cancer cells and to maintain their neoplastic metabolic state. Results show that silencing ERR significantly impaired colon cancer cell proliferation and colony formation in vitro as well as their in vivo tumorigenic capacity. A pronounced delay in G(1)-to-S cell cycle phase transition was observed in ERR-depleted cells in association with reduced cyclin-dependent kinase 2 activity and hyperphosphorylated state of the retinoblastoma protein along with disturbed expression of several cell cycle regulators, including p15 and p27. Interestingly, ERR-depleted HCT116 cells also displayed significant reduction in expression of a large set of key genes to glycolysis, tricarboxylic acid cycle and lipid synthesis. Furthermore, using C-14 isotope tracer analysis, ERR depletion in colon cancer cells resulted in reduced glucose incorporation and glucose-mediated lipogenesis in these cells. These findings suggest that ERR coordinates colon cancer cell proliferation and tumorigenic capacity with energy metabolism. Thus, ERR could represent a promising therapeutic target in colon cancer.