Reciprocal roles of DBC1 and SIRT1 in regulating estrogen receptor α activity and co-activator synergy

Estrogen receptor alpha (ER alpha) plays critical roles in development and progression of breast cancer. Because ER alpha activity is strictly dependent upon the interaction with coregulators, coregulators are also believed to contribute to breast tumorigenesis. Cell Cycle and Apoptosis Regulator 1 (CCAR1) is an important co-activator for estrogen-induced gene expression and estrogen-dependent growth of breast cancer cells. Here, we identified Deleted in Breast Cancer 1 (DBC1) as a CCAR1 binding protein. DBC1 was recently shown to function as a negative regulator of the NAD-dependent protein deacetylase SIRT1. DBC1 associates directly with ER alpha and cooperates synergistically with CCAR1 to enhance ER alpha function. DBC1 is required for estrogen-induced expression of a subset of ER alpha target genes as well as breast cancer cell proliferation and for estrogen-induced recruitment of ER alpha to the target promoters in a gene-specific manner. The mechanism of DBC1 action involves inhibition of SIRT1 interaction with ER alpha and of SIRT1-mediated deacetylation of ER alpha. SIRT1 also represses the co-activator synergy between DBC1 and CCAR1 by binding to DBC1 and disrupting its interaction with CCAR1. Our results indicate that DBC1 and SIRT1 play reciprocal roles as major regulators of ER alpha activity, by regulating DNA binding by ER alpha and by regulating co-activator synergy.