Zyxin cooperates with PTOV1 to confer retinoic acid resistance by repressing RAR activity.

Retinoids including all-trans retinoic acid (RA) have been widely used for cancer therapy. However, the major obstacle for RA therapy is the acquired resistance of which mechanism remained obscure thus far. Here, we first identified Zyxin that cooperates with PTOV1 for the negative regulation of RA signaling. Our studies on the underlying mechanism indicated that Zyxin, translocating to the nucleus in response to RA, mediates RAR repression by forming a ternary complex with PTOV1 and the RAR coactivator CBP, thereby promoting dissociation of CBP from RAR at the RA-responsive promoter. Consistently, RA-induced cancer cell cytotoxicity was significantly impaired by Zyxin or PTOV1. Overall, our findings suggest that Zyxin and PTOV1 should be considered as critical determinants in cancer therapy with retinoids.