Negative regulation of the deacetylase SIRT1 by DBC1.

Institute for Cancer Genetics, and Department of Pathology College of Physicians and Surgeons, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA.
Nature (Impact Factor: 42.35). 02/2008; 451(7178):587-90. DOI: 10.1038/nature06515
Source: PubMed

ABSTRACT SIRT1 is an NAD-dependent deacetylase critically involved in stress responses, cellular metabolism and, possibly, ageing. The tumour suppressor p53 represents the first non-histone substrate functionally regulated by acetylation and deacetylation; we and others previously found that SIRT1 promotes cell survival by deacetylating p53 (refs 4-6). These results were further supported by the fact that p53 hyperacetylation and increased radiation-induced apoptosis were observed in Sirt1-deficient mice. Nevertheless, SIRT1-mediated deacetylase function is also implicated in p53-independent pathways under different cellular contexts, and its effects on transcriptional factors such as members of the FOXO family and PGC-1alpha directly modulate metabolic responses. These studies validate the importance of the deacetylase activity of SIRT1, but how SIRT1 activity is regulated in vivo is not well understood. Here we show that DBC1 (deleted in breast cancer 1) acts as a native inhibitor of SIRT1 in human cells. DBC1-mediated repression of SIRT1 leads to increasing levels of p53 acetylation and upregulation of p53-mediated function. In contrast, depletion of endogenous DBC1 by RNA interference (RNAi) stimulates SIRT1-mediated deacetylation of p53 and inhibits p53-dependent apoptosis. Notably, these effects can be reversed in cells by concomitant knockdown of endogenous SIRT1. Our study demonstrates that DBC1 promotes p53-mediated apoptosis through specific inhibition of SIRT1.


Available from: Jun Qin, Apr 02, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent reports have shown that deleted in breast cancer 1 (DBC1/CCAR2) is an indicator of poor prognosis of various human cancers. However, its expression in ovarian carcinoma has not been reported. We investigated the immunohistochemical expression of DBC1 and BRCA1 and their prognostic significance in 104 ovarian carcinomas. Survival analyses were performed according to the Kaplan-Meier method, as well as univariate and multivariate Cox proportional hazard regression analysis. Positive expression of DBC1 and BRCA1 were seen in 63% (66/104) and 44% (46/104) of overall ovarian carcinomas, respectively. DBC1 expression was significantly associated with advanced clinicopathological factors such as high tumor stage, latent distant metastasis, platinum-resistance, elevated serum levels of CA125, high histologic grade, and BRCA1 expression. In the histological subtypes of ovarian carcinomas, DBC1 expression was more common in serous carcinoma (72%, 54/75) than mucinous carcinoma (15%, 3/20). BRCA1 expression was significantly associated with latent distant metastasis, platinum-resistance, and higher histologic grade. In addition, DBC1 expression was significantly associated with shorter overall survival (OS) and relapse-free survival (RFS) in 104 ovarian carcinomas (OS; P < 0.001, RFS; P < 0.001) and 63 high-grade serous carcinomas (OS; P = 0.008, RFS; P = 0.023) by univariate analysis. BRCA1 expression was significantly associated with OS and RFS in 104 ovarian carcinomas (OS; P = 0.005, RFS; P = 0.002) and 75 serous carcinomas (OS; P = 0.047, RFS; P = 0.038) by univariate analysis. Moreover, DBC1 expression was an independent prognostic indicator for OS in both 104 ovarian carcinomas (P = 0.021) and 63 high-grade serous carcinomas (P = 0.011) by multivariate analysis. These results indicate that the expression of DBC1 and BRCA1 are closely related with in the progression of ovarian carcinomas and may have clinical utility in the prediction of prognosis of ovarian carcinomas. Especially, DBC1 expression could be employed as a significant prognostic indicator for ovarian carcinomas especially in high-grade serous carcinomas.
    Journal of Ovarian Research 12/2015; 8(1). DOI:10.1186/s13048-015-0129-3 · 2.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Liver X receptors (LXRs) monitor endogenous sterol levels to maintain whole-body cholesterol levels and regulate inflammatory responses. Recent studies have demonstrated that LXRs may inhibit cellular proliferation, but the underlying mechanism remains unclear. Cell cycle and apoptosis regulator 2 (CCAR2), previously known as DBC1/KIAA1967, is a transcriptional regulator that regulates cellular proliferation and energy metabolism by inhibiting sirtuin 1 (SIRT1) deacetylase. Based on the findings that CCAR2 regulates several nuclear receptors, including the estrogen receptors and androgen receptor, we aimed to identify the underlying mechanism of CCAR2 regulation of LXRα. We found that CCAR2 formed a complex with LXRα in a ligand-independent manner in HepG2 cells, and in vitro pull-down assays, it revealed a direct interaction between the amino terminus of CCAR2 and the AF-2 domain of LXRα. Thereby, CCAR2 attenuates the ligand-dependent transcriptional activation function of LXRα. RNA interference-mediated depletion of endogenous CCAR2 potentiated the expression of the LXRα target genes ATP-binding cassette transporter A1 and G1, and the abrogation of CCAR2 resulted in decreased cellular proliferation. Moreover, competitive immunoprecipitation studies revealed that the LXRα downregulation involves the inhibition of SIRT1-LXRα complex formation. Therefore, these results clearly indicate a novel mechanism in which CCAR2 may regulate the transcriptional activation function of LXRα due to its specific inhibition of SIRT1 and serve to regulate cellular proliferation. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Journal of Steroid Biochemistry and Molecular Biology 02/2015; 149C:80-88. DOI:10.1016/j.jsbmb.2015.02.001 · 4.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective To investigate the possible role of deleted in breast cancer 1 (DBC1) in adipocyte and adipose tissue inflammation.Methods In vitro knockdown experiments using shRNA-lentiviral particles were performed to investigate the effect of DBC1 on adipocyte inflammation, sirtuin 1 (Sirt1) activity, and the AMPK pathway. The relationship between DBC1 and inflammation in human adipose tissue also was examined in two independent cohorts.ResultsDbc1 knockdown (KD) led to a significant reduction in the expression of inflammatory genes (Tnf, Il6, Stamp2, Lbp, and Mcp1) and pSer536NF-κB (p65)/NF-κB (p65) ratio in fully differentiated adipocytes. Of note, Dbc1 KD increased Sirt1 and AMPK activity in the early stage of adipocyte differentiation. In morbidly obese participants, DBC1 was positively correlated to TNF and senescence (TP53 and BAX) gene expression markers in both subcutaneous and visceral adipose tissues. Multivariate regression analysis revealed that senescence-related gene markers were the best predictors of adipose tissue DBC1 mRNA levels.ConclusionsDBC1 induced the expression of nuclear factor kappa B (NF-κB)-regulated inflammatory cytokines in fully differentiated 3T3-L1 adipocytes, possibly through the inhibition of Sirt1 activity, being significantly associated with human adipose tissue senescence in morbidly obese subjects.
    Obesity 02/2015; DOI:10.1002/oby.20999 · 4.39 Impact Factor