title: hnRNPA2/B1 activates cyclooxygenase-2 and promotes tumor growth in human lung cancers.
abstract: Cyclooxygenase-2 (COX-2) is highly expressed in tumor cells and has been regarded as a hallmarker for cancers, but the excise regulatory mechanism of COX-2 in tumorigenesis remains largely unknown. Here, we pulled down and identified a novel COX-2 regulator, heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1), which could specifically bind to COX-2 core promoter and regulate tumor growth in non-small-cell lung cancers (NSCLCs). Knockdown of hnRNPA2/B1 by shRNA or siRNA downregulated COX-2 expression and prostaglandin E2 (PGE2) production, and suppressed tumor cell growth in NSCLC cells in vitro and in vivo. Conversely, overexpression of hnRNPA2/B1 up-regulated the levels of COX-2 and PGE2 and promoted tumor cell growth. We also showed that hnRNPA2/B1 expression was positively correlated with COX-2 expression in NSCLC cell lines and tumor tissues, and the up-regulated expression of hnRNPA2/B1 and COX-2 predicted worse prognosis in NSCLC patients. Furthermore, we demonstrated that the activation of COX-2 expression by hnRNPA2/B1 was mediated through the cooperation with p300, a transcriptional co-activator, in NSCLC cells. The hnRNPA2/B1 could interact with p300 directly and be acetylated by p300. Exogenous overexpression of p300, but not its histone acetyltransferase (HAT) domain deletion mutation, augmented the acetylation of hnRNPA2/B1 and enhanced its binding on COX-2 promoter, thereby promoted COX-2 expression and lung cancer cell growth. Collectively, our results demonstrate that hnRNPA2/B1 promotes tumor cell growth by activating COX-2 signaling in NSCLC cells and imply that the hnRNPA2/B1/COX-2 pathway may be a potential therapeutic target for human lung cancers.
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China; The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xuan
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.
authors.forename: Jingshu
authors.initials: J
authors.lastname: Wang
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Liying
authors.initials: L
authors.lastname: Ban
authors.affiliation: Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Lu
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Canhui
authors.initials: C
authors.lastname: Yi
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Li
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Wendan
authors.initials: W
authors.lastname: Yu
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Xu
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Yang
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Tang
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Ranran
authors.initials: R
authors.lastname: Tang
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Xiao
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Songshu
authors.initials: S
authors.lastname: Meng
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China; The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China; State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, PR China.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China. Electronic address: cxn23@sina.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China. Electronic address: wei1015@dmu.edu.cn.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Cui
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China; State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, PR China. Electronic address: dengwg@sysucc.org.cn.
authors.forename: Wuguo
authors.initials: W
authors.lastname: Deng
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation
chemical_list: D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D009363:Neoplasm Proteins; C439768:hnRNP A2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: COX-2; Lung cancer; hnRNPA2/B1; p300