Department of Health Sciences and Technology, Sungkyunkwan University, Seoul 135-710, Korea.
Nucleic Acids Res. 2011 Sep 1;39(16):6932-43. doi: 10.1093/nar/gkr347. Epub 2011 May 19.
Estrogen receptor α (ERα) plays critical roles in development and progression of breast cancer. Because ERα 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 ERα and cooperates synergistically with CCAR1 to enhance ERα function. DBC1 is required for estrogen-induced expression of a subset of ERα target genes as well as breast cancer cell proliferation and for estrogen-induced recruitment of ERα to the target promoters in a gene-specific manner. The mechanism of DBC1 action involves inhibition of SIRT1 interaction with ERα and of SIRT1-mediated deacetylation of ERα. 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 ERα activity, by regulating DNA binding by ERα and by regulating co-activator synergy.
雌激素受体 α（ERα）在乳腺癌的发生和发展中起着关键作用。由于 ERα 的活性严格依赖于与共激活因子的相互作用，因此共激活因子也被认为有助于乳腺癌的发生。细胞周期和凋亡调节因子 1（CCAR1）是雌激素诱导的基因表达和雌激素依赖性乳腺癌细胞生长的重要共激活因子。在这里，我们鉴定出缺失乳腺癌 1（DBC1）是 CCAR1 的结合蛋白。最近研究表明，DBC1 作为 NAD 依赖性蛋白去乙酰化酶 SIRT1 的负调节因子发挥作用。DBC1 直接与 ERα 结合，并与 CCAR1 协同作用，增强 ERα 的功能。DBC1 是雌激素诱导的一组 ERα 靶基因表达以及乳腺癌细胞增殖所必需的，并且以基因特异性方式诱导 ERα 募集到靶启动子。DBC1 的作用机制涉及抑制 SIRT1 与 ERα 的相互作用以及 SIRT1 介导的 ERα 去乙酰化。SIRT1 通过与 DBC1 结合并破坏其与 CCAR1 的相互作用，也抑制 DBC1 和 CCAR1 之间的共激活因子协同作用。我们的结果表明，DBC1 和 SIRT1 通过调节 ERα 的 DNA 结合和调节共激活因子协同作用，作为 ERα 活性的主要调节因子，发挥相互作用。
