151. Transcriptional coactivator CBP upregulates hTERT expression and tumor growth and predicts poor prognosis in human lung cancers
- Author
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Wei Guo, Xiangsheng Xiao, Yao Xiao, Wangbing Chen, Wuguo Deng, Wendan Yu, Taihua Wu, Yuhui Yuan, Meng Dai, Quentin Liu, Jianjun Lu, Guangwei Du, Tingting Xu, Canhui Yi, Jingshu Wang, Zhipeng Tang, Dingbo Shi, and Zhenlong Yu
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Telomerase ,Lung Neoplasms ,Transcription, Genetic ,cells ,medicine.disease_cause ,Mice ,RNA, Small Interfering ,Promoter Regions, Genetic ,biology ,Acetylation ,Prognosis ,CREB-Binding Protein ,Gene Expression Regulation, Neoplastic ,Oncology ,embryonic structures ,Adenocarcinoma ,RNA Interference ,biological phenomena, cell phenomena, and immunity ,hTERT ,Protein Binding ,Research Paper ,Transcriptional Activation ,Cell Survival ,Sp1 Transcription Factor ,Transplantation, Heterologous ,Mice, Nude ,Adenocarcinoma of Lung ,CBP ,Sp1 ,Cancer stem cell ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Telomerase reverse transcriptase ,CREB-binding protein ,Lung cancer ,neoplasms ,Cell Proliferation ,promoter ,medicine.disease ,Molecular biology ,Transplantation ,enzymes and coenzymes (carbohydrates) ,lung cancer ,biology.protein ,Cancer research ,Carcinogenesis ,Neoplasm Transplantation - Abstract
// Wei Guo 1,* , Jianjun Lu 3,* , Meng Dai 1 , Taihua Wu 1 , Zhenlong Yu 1 , Jingshu Wang 2 , Wangbing Chen 2 , Dingbo Shi 2 , Wendan Yu 1 , Yao Xiao 1 , Canhui Yi 1 , Zhipeng Tang 1 , Tingting Xu 1 , Xiangsheng Xiao 2 , Yuhui Yuan 1 , Quentin Liu 1,2 , Guangwei Du 4 and Wuguo Deng 1,2 1 Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China 2 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Colaborative Innovation Center of Cancer Medicine, Guangzhou, China 3 Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China 4 Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA * These authors contributed equally to this work Correspondence: Wuguo Deng, email: // Wei Guo, email: // Keywords : CBP, hTERT, promoter, Sp1, lung cancer Received : July 17, 2014 Accepted : September 02, 2014 Published : September 03, 2014 Abstract Upregulated expression and activation of human telomerase reverse transcriptase (hTERT) is a hallmarker of lung tumorigenesis. However, the mechanism underlying the aberrant hTERT activity in lung cancer cells remains poorly understood. In this study, we found the transcriptional co-activator CBP as a new hTERT promoter-binding protein that regulated hTERT expression and tumor growth in lung adenocarcinoma cells using a biotin-streptavidin-bead pulldown technique. Chromatin immunoprecipitation assay verified the immortalized cell and tumor cell-specific binding of CBP on hTERT promoter. Overexpression of exogenous CBP upregulated the expression of the hTERT promoter-driven luciferase and endogenous hTERT protein in lung cancer cells. Conversely, inhibition of CBP by CBP-specific siRNA or its chemical inhibitor repressed the expression of hTERT promoter-driven luciferase and endogenous hTERT protein as well as telomerase activity. Moreover, inhibition of CBP expression or activity also significantly reduced the proliferation of lung cancer cells in vitro and tumor growth in an xenograft mouse model in vivo . Immunohistochemical analysis of tissue microarrays of lung cancers revealed a positive correlation between CBP and hTERT. Importantly, the patients with high CBP and hTERT expression had a significantly shorter overall survival. Furthermore, CBP was found to interact with and acetylate transactivator Sp1 in lung cancer cells. Inhibition of CBP by CBP-specific siRNA or its chemical inhibitor significantly inhibited Sp1 acetylation and its binding to the hTERT promoter. Collectively, our results indicate that CBP contributes to the upregulation of hTERT expression and tumor growth, and overexpression of CBP predicts poor prognosis in human lung cancers.
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- 2014