SUMOylation of ZFP282 potentiates its positive effect on estrogen signaling in breast tumorigenesis

Estrogen receptor alpha (ER alpha) has critical roles in the development and progression of breast cancer, and the coiled-coil co-activator (CoCoA) is an important ER alpha co-activator for estrogen-induced gene expression. The small ubiquitin-like modifier (SUMO) pathway is hyperactivated in breast cancer, but the mechanism by which SUMOylation regulates ER alpha-mediated transcription remains poorly understood. Here, we identified ZFP282 as a CoCoA-binding protein. ZFP282 associates directly with ER alpha and cooperates synergistically with CoCoA to enhance ER alpha function. ZFP282 is required for estrogen-induced expression of ER alpha target genes and estrogen-dependent breast cancer cell growth and tumorigenesis. In addition, we found that ZFP282 is SUMOylated and that SUMOylation positively regulates the co-activator activity of ZFP282 by increasing its binding affinity to ER alpha and CoCoA, and consequently increasing recruitment of ZFP282-CoCoA complex to the promoter of ER alpha target genes. These findings reveal essential roles for ZFP282 and its SUMOylation in estrogen signaling and breast tumorigenesis.