title: Ku80 cooperates with CBP to promote COX-2 expression and tumor growth.
abstract: 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.
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Yao
authors: Y
authors: Xiao
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors: Jingshu
authors: J
authors: Wang
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Yu
authors: Y
authors: Qin
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Yang
authors: Y
authors: Xuan
authors: Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors: Yunlu
authors: Y
authors: Jia
authors: Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors: Wenxian
authors: W
authors: Hu
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Wendan
authors: W
authors: Yu
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Meng
authors: M
authors: Dai
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Zhenglin
authors: Z
authors: Li
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Canhui
authors: C
authors: Yi
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Shilei
authors: S
authors: Zhao
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Mei
authors: M
authors: Li
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Sha
authors: S
authors: Du
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Wei
authors: W
authors: Cheng
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors: Xiangsheng
authors: X
authors: Xiao
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Yiming
authors: Y
authors: Chen
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Taihua
authors: T
authors: Wu
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Songshu
authors: S
authors: Meng
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Yuhui
authors: Y
authors: Yuan
authors: 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, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors: Quentin
authors: Q
authors: Liu
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
authors: Wenlin
authors: W
authors: Huang
authors: Institute of Cancer Stem Cell & First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors: Wei
authors: W
authors: Guo
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors: Shusen
authors: S
authors: Wang
authors: 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, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
authors: Wuguo
authors: W
authors: Deng
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D064593:Heterografts; D006801:Humans; D000072200:Ku Autoantigen; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011897:Random Allocation; D014162:Transfection
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen
keywords: CBP; COX-2; Ku80; lung cancer