Objective:To explore the expression of nuclear receptor corepressor (NCoR) in androgen independence prostate cancer (AIPC) and its clinical significance. Methods:The expression of NCoR and androgen receptor (AR) in pr...Objective:To explore the expression of nuclear receptor corepressor (NCoR) in androgen independence prostate cancer (AIPC) and its clinical significance. Methods:The expression of NCoR and androgen receptor (AR) in prostatic tissues, from 15 cases with AIPC, 20 cases with androgen dependence prostate cancer (ADPC) and 20 cases with benign prostatic hyperplasia (BPH), was detected by immunohistochemistry respectively. Results:The expression of NCoR was observed mainly in the nucleus and slightly in the nucleus. The positive cell percentage of NCoR in AIPC was significantly lower than that in ADPC and BPH (P<0.01). The NCoR expression was significantly lower in low differentiation prostate cancer (Pca) than that in high differentiation Pca (P<0.05). The rate of NCoR expression was significantly higher in low stage Pca than that in high stage Pca (P<0.05). AR, expressing in the nucleus, was found to be negative in one case of AIPC, while was strongly expressed in other cases of AIPC, and all cases of ADPC and BPH. Conclusion: The transition to AIPC of Pca may be correlated with the decrease of NCoR protein.展开更多
Background Estrogen receptor alpha （ER α） is the most important endocrine therapy responsiveness predictor for women with breast cancer. The accuracy of the prediction of the response to endocrine therapy was thoug...Background Estrogen receptor alpha （ER α） is the most important endocrine therapy responsiveness predictor for women with breast cancer. The accuracy of the prediction of the response to endocrine therapy was thought to be affected by involving the estrogen receptor coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. Nuclear corepressor 1 （NCOR1） is one of the ER a transcription repressor. The objective of the study is to investigate the expression of NCOR1 at the protein level and pursue its predictive value for breast cancer endocrine therapy. Methods In the present study, the level of expression of NCOR1 protein has been assessed by immunohistochemistry in 104 cases of invasive carcinoma of the breast. Associations between NCOR1 protein expression and different clinicopathological factors and survival were sought. Results It was found that NCOR1 was expressed at significantly higher levels in responsive patients treated with endocrine therapy as first-line treatment on relapse. Responsive patients also had a significantly longer post-relapse survival and overall survival. No NCOR1 expression difference was found between patient by age, tumor size, lymph node status, different histological grade groups and human epidermal growth factor receptor 2 （HER2） status. Multivariate analysis showed that NCOR1 is an independent prognostic factor for over-all survival. Conclusions In breast cancer, NCOR1 protein expression level predicts response to endocrine therapy as first-line treatment for breast cancer patients on relapse and NCOR1 protein level assay may increase the accuracy in the endocrine treatment determination and, therefore, improving the patients survival.展开更多
Background NF-KB p65 was shown to inhibit transcription of phosphoenolpyruvate carboxykinase （PEPCK）, a rate-limiting enzyme in gluconeogenesis in the liver. To understand the mechanism of action of NF-KB p65, we in...Background NF-KB p65 was shown to inhibit transcription of phosphoenolpyruvate carboxykinase （PEPCK）, a rate-limiting enzyme in gluconeogenesis in the liver. To understand the mechanism of action of NF-KB p65, we investigated the nuclear receptor corepressor in the regulation of PEPCK transcription. Methods Rat H411E cells, human hepatoma HepG2 cells and human embryo kidney （HEK） 293 cells were used in this study. The transcriptional activity of a rat PEPCK gene promoter （-490/＋100） was analyzed in HepG2 cells, a HepG2 super suppressor IkBa （sslkBa） stable cell line, and HEK 293 cells. The effects of p65 and sslkBa on a rat PEPCK gene promoter were observed using the PEPCK luciferase reporter system. The interaction of the cAMP-response- element-binding （CREB） protein, histone deacetylase 3 （HDAC3） and silencing mediator for retinoic and thyroid hormone receptors （SMRT） with the PEPCK gene promoter were investigated using the chromatin immunoprecipitation （CHIP） assay, p65 cotransfection and RNAi-mediated gene knockdown were used to determine the corepressor involved in the inhibition of PEPCK by NF-KB p65 and the transcriptional regulation of CREB by NF-KB p65. Results NF-KB p65 inhibited PEPCK expression and the inhibition was blocked by sslkBa. The inhibitory effect of p65 was completely blocked in a HepG2 stable cell line in which sslkBa was expressed. HDAC3 or SMRT knockdown led to a significant up-regulation of PEPCK reporter activity in the presence of p65 cotransfection. In the ChIP assay the interaction of HDAC3 and SMRT with the PEPCK gene promoter was induced by p65 activation, but the CREB signal was reduced. Transcriptional activity of CREB was inhibited by NF-kB p65 cotransfection. The inhibitory effect of NF-kB p65 was blocked by HDAC3 RNAi or SMRT RNAi. Conculsions The study showed that the inhibition of PEPCK by NF-kB p65 was dependent on HDAC3 and SMRT, which form a nuclear corepressor complex for transcriptional inhibition. The transcription factors NF-kB p65 and CREB share the same corepressor HDAC3-SMRT, and the corepressor exchange leads to inhibition of PEPCK gene transcription by NF-kB p65.展开更多
Coactivators and corepressors regulate transcriptionby controlling interactions between sequence-specific transcription factors, the basal transcriptional machinery andthe chromatin environment. This review consider t...Coactivators and corepressors regulate transcriptionby controlling interactions between sequence-specific transcription factors, the basal transcriptional machinery andthe chromatin environment. This review consider the access of nuclear and steroid receptors to chromatin, theiruse of corepressors and coactivators to modify chromatinstructure and the implications for transcriptional control.The assembly of specific nucleoprotein architectures andtargeted histone modification emerge as central controlling elements for gene expression.展开更多
文摘Objective:To explore the expression of nuclear receptor corepressor (NCoR) in androgen independence prostate cancer (AIPC) and its clinical significance. Methods:The expression of NCoR and androgen receptor (AR) in prostatic tissues, from 15 cases with AIPC, 20 cases with androgen dependence prostate cancer (ADPC) and 20 cases with benign prostatic hyperplasia (BPH), was detected by immunohistochemistry respectively. Results:The expression of NCoR was observed mainly in the nucleus and slightly in the nucleus. The positive cell percentage of NCoR in AIPC was significantly lower than that in ADPC and BPH (P<0.01). The NCoR expression was significantly lower in low differentiation prostate cancer (Pca) than that in high differentiation Pca (P<0.05). The rate of NCoR expression was significantly higher in low stage Pca than that in high stage Pca (P<0.05). AR, expressing in the nucleus, was found to be negative in one case of AIPC, while was strongly expressed in other cases of AIPC, and all cases of ADPC and BPH. Conclusion: The transition to AIPC of Pca may be correlated with the decrease of NCoR protein.
文摘Background Estrogen receptor alpha （ER α） is the most important endocrine therapy responsiveness predictor for women with breast cancer. The accuracy of the prediction of the response to endocrine therapy was thought to be affected by involving the estrogen receptor coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. Nuclear corepressor 1 （NCOR1） is one of the ER a transcription repressor. The objective of the study is to investigate the expression of NCOR1 at the protein level and pursue its predictive value for breast cancer endocrine therapy. Methods In the present study, the level of expression of NCOR1 protein has been assessed by immunohistochemistry in 104 cases of invasive carcinoma of the breast. Associations between NCOR1 protein expression and different clinicopathological factors and survival were sought. Results It was found that NCOR1 was expressed at significantly higher levels in responsive patients treated with endocrine therapy as first-line treatment on relapse. Responsive patients also had a significantly longer post-relapse survival and overall survival. No NCOR1 expression difference was found between patient by age, tumor size, lymph node status, different histological grade groups and human epidermal growth factor receptor 2 （HER2） status. Multivariate analysis showed that NCOR1 is an independent prognostic factor for over-all survival. Conclusions In breast cancer, NCOR1 protein expression level predicts response to endocrine therapy as first-line treatment for breast cancer patients on relapse and NCOR1 protein level assay may increase the accuracy in the endocrine treatment determination and, therefore, improving the patients survival.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 30570885）, 973 Program of China （No. 2006CB503902） （to WENG Jian-ping）, the National Institutes of Health Grant （No. DK068036） and American Diabetes Association Research Award （No. 7-04-RA-139） （to YE ,lian-ping）Acknowledgements： We would like to be grateful to Ms. Wei Tseng, Dr. HE Qin and Dr. YIN Jun for their excellent technical assistance.
文摘Background NF-KB p65 was shown to inhibit transcription of phosphoenolpyruvate carboxykinase （PEPCK）, a rate-limiting enzyme in gluconeogenesis in the liver. To understand the mechanism of action of NF-KB p65, we investigated the nuclear receptor corepressor in the regulation of PEPCK transcription. Methods Rat H411E cells, human hepatoma HepG2 cells and human embryo kidney （HEK） 293 cells were used in this study. The transcriptional activity of a rat PEPCK gene promoter （-490/＋100） was analyzed in HepG2 cells, a HepG2 super suppressor IkBa （sslkBa） stable cell line, and HEK 293 cells. The effects of p65 and sslkBa on a rat PEPCK gene promoter were observed using the PEPCK luciferase reporter system. The interaction of the cAMP-response- element-binding （CREB） protein, histone deacetylase 3 （HDAC3） and silencing mediator for retinoic and thyroid hormone receptors （SMRT） with the PEPCK gene promoter were investigated using the chromatin immunoprecipitation （CHIP） assay, p65 cotransfection and RNAi-mediated gene knockdown were used to determine the corepressor involved in the inhibition of PEPCK by NF-KB p65 and the transcriptional regulation of CREB by NF-KB p65. Results NF-KB p65 inhibited PEPCK expression and the inhibition was blocked by sslkBa. The inhibitory effect of p65 was completely blocked in a HepG2 stable cell line in which sslkBa was expressed. HDAC3 or SMRT knockdown led to a significant up-regulation of PEPCK reporter activity in the presence of p65 cotransfection. In the ChIP assay the interaction of HDAC3 and SMRT with the PEPCK gene promoter was induced by p65 activation, but the CREB signal was reduced. Transcriptional activity of CREB was inhibited by NF-kB p65 cotransfection. The inhibitory effect of NF-kB p65 was blocked by HDAC3 RNAi or SMRT RNAi. Conculsions The study showed that the inhibition of PEPCK by NF-kB p65 was dependent on HDAC3 and SMRT, which form a nuclear corepressor complex for transcriptional inhibition. The transcription factors NF-kB p65 and CREB share the same corepressor HDAC3-SMRT, and the corepressor exchange leads to inhibition of PEPCK gene transcription by NF-kB p65.
文摘Coactivators and corepressors regulate transcriptionby controlling interactions between sequence-specific transcription factors, the basal transcriptional machinery andthe chromatin environment. This review consider the access of nuclear and steroid receptors to chromatin, theiruse of corepressors and coactivators to modify chromatinstructure and the implications for transcriptional control.The assembly of specific nucleoprotein architectures andtargeted histone modification emerge as central controlling elements for gene expression.
