CREB-binding protein regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathway
CREB-binding protein regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathway
复制标题
CREB 结合蛋白通过靶向 MAPK 和 CPSF4 信号通路调节肺癌生长。
DOI：
10.1016/j.molonc.2015.10.015
复制
发表时间：
2016-02-01
影响因子：
6.6
通讯作者：
Guo, Wei
中科院分区：
文献类型：
--
作者：
Tang, Zhipeng;Yu, Wendan;Guo, Wei
CBP（CREB-结合蛋白）是一种具有组蛋白乙酰转移酶（HAT）活性的转录辅激活因子，参与胚胎发育、生长调控和体内平衡等多种生物学过程。然而，其在调节癌发生和肿瘤发展中的作用和潜在机制在很大程度上仍然未知。在此，我们研究了CBP参与肺癌细胞生长和存活的分子机制和潜在靶点。与正常肺细胞和组织相比，在肺癌细胞和肿瘤组织中检测到CBP的表达升高。通过siRNA敲除CBP或使用特异性化学抑制剂抑制其HAT活性可有效抑制肺癌细胞的增殖、迁移和集落形成，并通过抑制MAPK和激活细胞色素C/caspase依赖的信号通路诱导肺癌细胞凋亡。免疫共沉淀和免疫荧光分析揭示了CBP和CPSF 4（裂解和多聚腺苷酸化特异性因子4）蛋白在肺癌细胞中的共定位和相互作用。CPSF 4的敲低抑制CBP诱导的hTERT转录和细胞生长，反之亦然，证明CBP和CPSF 4在调节肺癌细胞生长和存活中的协同作用。此外，我们发现CBP和CPSF 4的高表达预示着肺腺癌患者的预后不良。总的来说，我们的研究结果表明CBP通过靶向MAPK和CPSF 4信号通路调节肺癌生长。(C)2015年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
CBP (CREB-binding protein) is a transcriptional co-activator which possesses HAT (histone acetyltransferases) activity and participates in many biological processes, including embryonic development, growth control and homeostasis. However, its roles and the underlying mechanisms in the regulation of carcinogenesis and tumor development remain largely unknown. Here we investigated the molecular mechanisms and potential targets of CBP involved in tumor growth and survival in lung cancer cells. Elevated expression of CBP was detected in lung cancer cells and tumor tissues compared to the normal lung cells and tissues. Knockdown of CBP by siRNA or inhibition of its HAT activity using specific chemical inhibitor effectively suppressed cell proliferation, migration and colony formation and induced apoptosis in lung cancer cells by inhibiting MAPK and activating cytochrome C/caspase-dependent signaling pathways. Co-immunoprecipitation and immunofluorescence analyses revealed the co-localization and interaction between CBP and CPSF4 (cleavage and polyadenylation specific factor 4) proteins in lung cancer cells. Knockdown of CPSF4 inhibited hTERT transcription and cell growth induced by CBP, and vice versa, demonstrating the synergetic effect of CBP and CPSF4 in the regulation of lung cancer cell growth and survival. Moreover, we found that high expression of both CBP and CPSF4 predicted a poor prognosis in the patients with lung adenocarcinomas. Collectively, our results indicate that CBP regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathways. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.