Ku80 cooperates with CBP to promote COX-2 expression and tumor growth
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Yao Xiao1,*, Jingshu Wang2,*, Yu Qin1, Yang Xuan1, Yunlu Jia3, Wenxian Hu3, Wendan Yu1, Meng Dai1, Zhenglin Li1, Canhui Yi1, Shilei Zhao1, Mei Li1, Sha Du1, Wei Cheng1, Xiangsheng Xiao2, Yiming Chen1, Taihua Wu1, Songshu Meng1, Yuhui Yuan1, Quentin Liu1,2, Wenlin Huang2,4, Wei Guo1, Shusen Wang2 and Wuguo Deng1,2,4
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, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
3 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
4 State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China
* These authors contributed equally to this article
Shusen Wang, email:
Wei Guo, email:
Wuguo Deng, email:
Keywords: Ku80, CBP, COX-2, lung cancer
Received: December 30, 2014 Accepted: February 04, 2015 Published: March 08, 2015
Cyclooxygenase-2 (COX-2) plays an important role in lung cancer development and progression. Using streptavidin-agarose pulldown and proteomics assay, we identified and validated Ku80, a dimer of Ku participating in the repair of broken DNA double strands, as a new binding protein of the COX-2 gene promoter. Overexpression of Ku80 up-regulated COX-2 promoter activation and COX-2 expression in lung cancer cells. Silencing of Ku80 by siRNA down-regulated COX-2 expression and inhibited tumor cell growth in vitro and in a xenograft mouse model. Ku80 knockdown suppressed phosphorylation of ERK, resulting in an inactivation of the MAPK pathway. Moreover, CBP, a transcription co-activator, interacted with and acetylated Ku80 to co-regulate the activation of COX-2 promoter. Overexpression of CBP increased Ku80 acetylation, thereby promoting COX-2 expression and cell growth. Suppression of CBP by a CBP-specific inhibitor or siRNA inhibited COX-2 expression as well as tumor cell growth. Tissue microarray immunohistochemical analysis of lung adenocarcinomas revealed a strong positive correlation between levels of Ku80 and COX-2 and clinicopathologic variables. Overexpression of Ku80 was associated with poor prognosis in patients with lung cancers. We conclude that Ku80 promotes COX-2 expression and tumor growth and is a potential therapeutic target in lung cancer.
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