Journal
MOLECULAR ONCOLOGY
Volume 10, Issue 4, Pages 610-624Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.molonc.2015.11.010
Keywords
hnRNPA2/B1; COX-2; p300; Lung cancer
Categories
Funding
- National Natural Science Foundation of China [81173615 XC, 81470337 YC, 81472178 WD, 81372133 XX]
- State 973 Program of China [2014CB542005]
- State 863 Program of China [SS2012AA020403]
- Education Department of Liaoning Province in China (the Program for Pan-Deng Scholars)
- Natural Science Foundation of Liaoning Province in China [2014023009]
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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 (PGE(2)) 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 PGE(2) 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. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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