title: Transcriptional coactivator CBP upregulates hTERT expression and tumor growth and predicts poor prognosis in human lung cancers.
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.
authors.affiliation: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China. These authors contributed equally to this work.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. These authors contributed equally to this work.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Dai
authors.affiliation: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Taihua
authors.initials: T
authors.lastname: Wu
authors.affiliation: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Colaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Jingshu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Colaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Wangbing
authors.initials: W
authors.lastname: Chen
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Colaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Dingbo
authors.initials: D
authors.lastname: Shi
authors.affiliation: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Wendan
authors.initials: W
authors.lastname: Yu
authors.affiliation: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Canhui
authors.initials: C
authors.lastname: Yi
authors.affiliation: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Xu
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Colaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Colaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, USA.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Du
authors.affiliation: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Colaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Wuguo
authors.initials: W
authors.lastname: Deng
mesh_terms: D000107:Acetylation; D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D019098:Telomerase / Q000096:biosynthesis / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous
chemical_list: D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D050882:CREB-Binding Protein; C509186:TERT protein, human; D019098:Telomerase