Transcriptional coactivator CBP upregulates hTERT expression and tumor growth and predicts poor prognosis in human lung cancers.
Transcriptional coactivator CBP upregulates hTERT expression and tumor growth and predicts poor prognosis in human lung cancers.
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转录共激活因子 CBP 上调 hTERT 表达和肿瘤生长并预测人类肺癌的不良预后
DOI：
10.18632/oncotarget.2430
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发表时间：
2014-10-15
期刊：
影响因子：
--
通讯作者：
Deng W
中科院分区：
文献类型：
--
作者：
Guo W;Lu J;Dai M;Wu T;Yu Z;Wang J;Chen W;Shi D;Yu W;Xiao Y;Yi C;Tang Z;Xu T;Xiao X;Yuan Y;Liu Q;Du G;Deng W
人端粒酶逆转录酶（hTERT）的表达上调和激活是肺肿瘤发生的标志。然而，肺癌细胞中异常hTERT活性的潜在机制仍然知之甚少。在这项研究中，我们发现转录共激活CBP作为一种新的hTERT启动子结合蛋白，调节hTERT表达和肿瘤生长在肺腺癌细胞中使用生物素-链霉亲和素-珠下拉技术。染色质免疫沉淀实验证实CBP可特异性结合hTERT启动子上的永生化细胞和肿瘤细胞。外源CBP的过表达上调hTERT启动子驱动的荧光素酶和内源性hTERT蛋白在肺癌细胞中的表达。相反，CBP特异性siRNA或其化学抑制剂抑制CBP抑制hTERT启动子驱动的荧光素酶和内源性hTERT蛋白的表达以及端粒酶活性。此外，CBP表达或活性的抑制还显著降低了体外肺癌细胞的增殖和体内异种移植小鼠模型中的肿瘤生长。肺癌组织芯片的免疫组化分析显示CBP和hTERT呈正相关。重要的是，CBP和hTERT高表达的患者的总生存期明显缩短。此外，发现CBP与肺癌细胞中的反式激活因子Sp1相互作用并使其乙酰化。CBP特异性siRNA或其化学抑制剂抑制CBP可显著抑制Sp1乙酰化及其与hTERT启动子的结合。总的来说，我们的研究结果表明，CBP有助于上调hTERT表达和肿瘤生长，CBP的过度表达预测人类肺癌预后不良。
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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影响因子：
7.8
作者：
Bazarov AV;Van Sluis M;Hines WC;Bassett E;Beliveau A;Campeau E;Mukhopadhyay R;Lee WJ;Melodyev S;Zaslavsky Y;Lee L;Rodier F;Chicas A;Lowe SW;Benhattar J;Ren B;Campisi J;Yaswen P
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Yaswen P
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7.8
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影响因子：
3.7
作者：
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通讯作者：
Matsui, William
影响因子：
3.5
作者：
Cong, YS;Wen, JP;Bacchetti, S
通讯作者：
Bacchetti, S
影响因子：
23.9
作者：
Marion, Rosa M.;Strati, Katerina;Blasco, Maria A.
通讯作者：
Blasco, Maria A.