Orphan receptor COUP-TF is required for induction of retinoic acid receptor β, growth inhibition, and apoptosis by retinoic acid in cancer cells

Retinoic acid receptor beta (RAR beta) plays a critical role in mediating the anticancer effects of retinoids. Expression of RAR beta is highly induced by retinoic acid (RA) through a RA response element (beta RARE) that is activated by heterodimers of RARs and retinoid X receptors (RXRs). However, RAR beta induction is often lost in cancer cells despite expression of RARs and RXRs. In this study, we provide evidence that orphan receptor COUP-TF is required for induction of RAR beta expression, growth inhibition, and apoptosis by RA in cancer cells. Expression of COUP-TF correlates with RAR beta induction in a variety of cancer cell lines. In addition, stable expression of COUP-TF in COUP-TF-negative cancer cells restores induction of RAR beta expression, growth inhibition, and apoptosis by RA, whereas inhibition of COUP-TF by expression of COUP-TF antisense RNA represses the RA effects. In a transient transfection assay, COUP-TF strongly induced transcriptional activity of the RAR beta promoter in a RA- and RAR alpha-dependent manner. By mutation analysis, we demonstrate that the effect of COUP-TF requires its binding to a DR-8 element present in the RAR beta promoter. The binding of COUP;TF to the DR-8 element synergistically increases the RA-dependent RAR alpha transactivation function by enhancing the interaction of RAR alpha with its coactivator CREB binding protein. These results demonstrate that COUP-TF, by serving as an accessory protein for RAR alpha to induce RAR beta expression, plays a critical role in regulating the anticancer activities of retinoids.