Transcriptional coactivator CBP upregulates hTERT expression and tumor growth and predicts poor prognosis in human lung cancers
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Wei Guo1,*, Jianjun Lu3,*, Meng Dai1, Taihua Wu1, Zhenlong Yu1, Jingshu Wang2, Wangbing Chen2, Dingbo Shi2, Wendan Yu1, Yao Xiao1, Canhui Yi1, Zhipeng Tang1, Tingting Xu1, Xiangsheng Xiao2, Yuhui Yuan1, Quentin Liu1,2, Guangwei Du4 and Wuguo Deng1,2
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
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
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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