Identification of DBC1 as a transcriptional repressor for BRCA1

Abstract

BACKGROUND: DBC1/KIAA1967 (deleted in breast cancer 1) is a putative tumour-suppressor gene cloned from a heterozygously deleted region in breast cancer specimens. Caspase-dependent processing of DBC1 promotes apoptosis, and depletion of endogenous DBC1 negatively regulates p53-dependent apoptosis through its specific inhibition of SIRT1. Hereditary breast and ovarian cancer susceptibility gene product BRCA1, by binding to the promoter region of SIRT1, is a positive regulator of SIRT1 expression. METHODS: A physical interaction between DBC1 and BRCA1 was investigated both in vivo and in vitro. To determine the pathophysiological significance of DBC1, its role as a transcriptional factor was studied. RESULTS: We found a physical interaction between the amino terminus of DBC1 and the carboxyl terminus of BRCA1, also known as the BRCT domain. Endogenous DBC1 and BRCA1 form a complex in the nucleus of intact cells, which is exported to the cytoplasm during ultraviolet-induced apoptosis. We also showed that the expression of DBC1 represses the transcriptional activation function of BRCT by a transient expression assay. The expression of DBC1 also inhibits the transactivation of the SIRT1 promoter mediated by full-length BRCA1. CONCLUSION: These results revealed that DBC1 may modulate the cellular functions of BRCA1 and have important implications in the understanding of carcinogenesis in breast tissue.

Expression of DBC1 is associated with nuclear grade and HER2 expression in breast cancer

“…DBC1 has been found to associate with unliganded-ERα and to manipulate ligandindependent growth of breast cancer cells (23). Our previous data also indicated the possible tumorigenic role of DBC1 (8,9). However, given that DBC1 inhibits the deacetylase activity of SIRT1 and promotes p53-dependent apoptosis (5,6), DBC1 expression may not be directly associated with tumorigenesis.…”

“…They were subsequently treated with 0.3% hydrogen peroxide in methanol for 15 min to quench endogenous peroxidase activity. The primary antibodies were anti-DBC1 rabbit polyclonal antibody (produced in our laboratory) (8,9) and anti-SIRT1 rabbit polyclonal antibodies (H-300; Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA). These primary antibodies were diluted (DBC1 1/100,000; SIRT1 1/200), and the tissue sections were incubated for 30 min at room temperature using reagents provided with the ChemMate EnVision™ Detection system (Dako, Carpinteria, CA, USA).…”

“…Currently, the molecular and cellular functions of DBC1 are being extensively investigated to reveal its precise physiological role (5)(6)(7)(8)(9). The endogenous DBC1 is a nuclear protein and the amino-terminus of DBC1 has been shown to be a protein-interaction surface and DBC1 serves as a transcriptional factor to repress transcriptional activation function, such as BRCA1 (8) and estrogen receptor β (9). During TNF-α induced apoptosis, DBC1 is translocated to the cytoplasm with loss of the nuclear localization signal by caspase-dependent cleavage, and this cleavage promotes apoptosis due to the death-promoting activity of its carboxylterminal coiled-coil domain (7).…”

High SIRT1 expression and low DBC1 expression are associated with poor prognosis in colorectal cancer

“…Alternatively, DBC1 independently of SIRT1 might contribute to the growth or survival of cancer cells, as DBC1 interacts with various proteins including retinoic acid receptor-a, estrogen receptor-a and b, androgen receptor, SUV39H1 methyltransferase, histone deacetylase 3 (ref. 19 and references therein) as well as BRCA1 [34] and interaction between DBC1 and SIRT1 can be lost in some cases [35,36]. The roles of DCB1 in the growth of colorectal cancer cells, as well as participation to drug resistance, are currently under investigation.…”

Hereditary Pancreatic Cancer

“…The protein is associated with the BRCA1 associated genome surveillance complex (BASC) along with RNA polymerase II with the histone deacetlylase complexes. The protein plays a role in transcription along with DNA repair of double-strand breaks and recombination [15]. BRCA2 encodes for a protein that is also associated with double-strand break repair and homologous recombination.…”