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

ABSTRACT: Estrogen receptor ? (ER?) plays critical roles in development and progression of breast cancer. Because ER? 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? and cooperates synergistically with CCAR1 to enhance ER? function. DBC1 is required for estrogen-induced expression of a subset of ER? target genes as well as breast cancer cell proliferation and for estrogen-induced recruitment of ER? to the target promoters in a gene-specific manner. The mechanism of DBC1 action involves inhibition of SIRT1 interaction with ER? and of SIRT1-mediated deacetylation of ER?. 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? activity, by regulating DNA binding by ER? and by regulating co-activator synergy.

SUBMITTER: Yu EJ

PROVIDER: S-EPMC3167635 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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

Yu Eun Ji EJ Kim Seok-Hyung SH Heo Kyu K Ou Chen-Yin CY Stallcup Michael R MR Kim Jeong Hoon JH

Nucleic acids research 20110519 16

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 ...[more]

PMID: 21596782

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Project description:BACKGROUND: The placenta-specific 1 (PLAC1) gene encodes a membrane-associated protein which is selectively expressed in the placental syncytiotrophoblast and in murine fetal tissues during embryonic development. In contrast to its transcriptional repression in all other adult normal tissues, PLAC1 is frequently activated and highly expressed in a variety of human cancers, in particular breast cancer, where it associates with estrogen receptor ? (ER?) positivity. In a previous study, we showed that ER?-signaling in breast cancer cells transactivates PLAC1 expression in a non-classical pathway. As the members of the p160/nuclear receptor co-activator (NCOA) family, NCOA1, NCOA2 and NCOA3 are known to be overexpressed in breast cancer and essentially involved in estrogen-mediated cancer cell proliferation we asked if these proteins are involved in the ER?-mediated transactivation of PLAC1 in breast cancer cells. METHODS: Applying quantitative real-time RT-PCR (qRT-PCR), Western Blot analysis and chromatin immunoprecipitation, we analyzed the involvement of NCOA1, NCOA2, NCOA3 in the ER?-mediated transactivation of PLAC1 in the breast cancer cell lines MCF-7 and SK-BR-3. RNAi-mediated silencing of NCOA3, qRT-PCR, Western blot analysis and ER? activation assays were used to examine the role of NCOA3 in the ER?-mediated regulation of PLAC1 in further detail. Transcript expression of NCOA3 and PLAC1 in 48 human breast cancer samples was examined by qRT-PCR and statistical analysis was performed using Student's t-test. RESULTS: We detected selective recruitment of NCOA3 but not NCOA1 or NCOA2 to the PLAC1 promoter only in ER?-positive MCF-7 cells but not in ER?-negative SK-BR-3 breast cancer cells. In addition, we demonstrate that silencing of NCOA3 results in a remarkable decrease of PLAC1 expression levels in MCF-7 cells which cannot be restored by treatment with estradiol (E?). Moreover, significant higher transcript levels of PLAC1 were found only in ER?-positive human breast cancer samples which also show a NCOA3 overexpression. CONCLUSIONS: In this study, we identified NCOA3 as a selective co-activator of ER?-mediated transactivation of PLAC1 in MCF-7 breast cancer cells. Our data introduce PLAC1 as novel target gene of NCOA3 in breast cancer, supporting the important role of both factors in breast cancer biology.

Dataset Information

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

Publications

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

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