Journal Article
. 2004 Feb; 279(18):18694-700.
doi: 10.1074/jbc.M308136200.

Polyoma enhancer activator 3, an ets transcription factor, mediates the induction of cyclooxygenase-2 by nitric oxide in colorectal cancer cells

Yongmin Liu 1 Gregory L Borchert  James M Phang  
  • PMID: 14976201
  •     22 citations


Abundant evidence supports the role of cyclooxygenase-2 (COX-2) in colorectal cancer. Nitric oxide (NO), a pro-inflammatory signaling factor, may regulate COX-2 expression and activity thereby linking hyper-inflammatory states to cancer susceptibility. Previously we showed that NO induced COX-2 expression. Although NO also activated the beta-catenin.T-cell factor/lymphocyte enhancing factor transcriptional pathway, a direct causal link between this pathway and COX-2 expression was not demonstrated. In this current study, we focused on NO-induced transcriptional activity and elucidated its role in COX-2 expression. NO donors stimulated the expression of peroxisome proliferator-activated receptor-delta and c-myc, both downstream genes of beta-catenin. They also induced the expression of polyoma enhancer activator 3 (PEA3) and increased its DNA-binding activity. To establish a role for PEA3 to beta-catenin-induced COX-2, we transfected RKO cells with beta-catenin and found that beta-catenin increased PEA3 expression. Also, there was higher PEA3 in immortal mouse colon epithelium cells (Apc(Min/)(+)) compared with young adult mouse colon cells (Apc(+/+)). Luciferase reporter assays revealed that, although several transcription factors/coactivator, acting alone or in synergistic combination, induced COX-2 promoter activity, PEA3 was one of the most potent. Interestingly, NO from NO donors or generated endogenously from transfected inducible nitric-oxide synthase, increased PEA3/p300-induced COX-2 promoter activity. We also found that an ETS site (-75/-72) and the NF-IL6 site were responsible for COX-2 activity induced by PEA3, PEA3/p300, and NO. Taken together, our results demonstrated that NO through beta-catenin signaling stimulated PEA3 to increase COX-2 activity. In addition, NO augmented the synergistic interaction between PEA3 and CBP/p300.

Gene expression profiling of colorectal adenomas and early invasive carcinomas by cDNA array analysis.
K Nosho, H Yamamoto, +3 authors, K Imai.
Br J Cancer, 2005 Mar 24; 92(7). PMID: 15785755    Free PMC article.
Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development.
Lawryn H Kasper, Tomofusa Fukuyama, +6 authors, Paul K Brindle.
Mol Cell Biol, 2006 Jan 24; 26(3). PMID: 16428436    Free PMC article.
Hepatocyte growth factor regulates cyclooxygenase-2 expression via beta-catenin, Akt, and p42/p44 MAPK in human bronchial epithelial cells.
Young H Lee, Yuichiro J Suzuki, Autumn J Griffin, Regina M Day.
Am J Physiol Lung Cell Mol Physiol, 2008 Feb 05; 294(4). PMID: 18245266    Free PMC article.
Ets transcription factors in intestinal morphogenesis, homeostasis and disease.
Paul Jedlicka, Arthur Gutierrez-Hartmann.
Histol Histopathol, 2008 Sep 12; 23(11). PMID: 18785124    Free PMC article.
Extracellular signal-regulated kinase mitogen-activated protein kinase signaling initiates a dynamic interplay between sumoylation and ubiquitination to regulate the activity of the transcriptional activator PEA3.
Baoqiang Guo, Andrew D Sharrocks.
Mol Cell Biol, 2009 Mar 25; 29(11). PMID: 19307308    Free PMC article.
Negative regulation of fibroblast growth factor 10 (FGF-10) by polyoma enhancer activator 3 (PEA3).
Athina-Myrto Chioni, Richard Grose.
Eur J Cell Biol, 2009 May 05; 88(7). PMID: 19410332    Free PMC article.
LKB1/PEA3/ΔNp63 pathway regulates PTGS-2 (COX-2) transcription in lung cancer cells upon cigarette smoke exposure.
Edward A Ratovitski.
Oxid Med Cell Longev, 2010 Dec 15; 3(5). PMID: 21150337    Free PMC article.
Expression of osteopontin coregulators in primary colorectal cancer and associated liver metastases.
D J Mole, C O'Neill, +6 authors, F C Campbell.
Br J Cancer, 2011 Feb 24; 104(6). PMID: 21343932    Free PMC article.
PEA3/ETV4-related transcription factors coupled with active ERK signalling are associated with poor prognosis in gastric adenocarcinoma.
R Keld, B Guo, +4 authors, A D Sharrocks.
Br J Cancer, 2011 Jun 16; 105(1). PMID: 21673681    Free PMC article.
The role of nitric oxide in prostaglandin biology; update.
Sangwon F Kim.
Nitric Oxide, 2011 Aug 09; 25(3). PMID: 21820072    Free PMC article.
Nitric oxide and protein phosphatase 2A provide novel therapeutic opportunities in ER-negative breast cancer.
Christopher H Switzer, Sharon A Glynn, +4 authors, David A Wink.
Trends Pharmacol Sci, 2011 Sep 07; 32(11). PMID: 21893353    Free PMC article.
Synthetic transactivation screening reveals ETV4 as broad coactivator of hypoxia-inducible factor signaling.
Kristin Wollenick, Jun Hu, +6 authors, Daniel P Stiehl.
Nucleic Acids Res, 2011 Nov 15; 40(5). PMID: 22075993    Free PMC article.
ETV1, 4 and 5: an oncogenic subfamily of ETS transcription factors.
Sangphil Oh, Sook Shin, Ralf Janknecht.
Biochim Biophys Acta, 2012 Mar 20; 1826(1). PMID: 22425584    Free PMC article.
Highly Cited. Review.
Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: relevance and clinical implications.
Daniela Salvemini, Sangwon F Kim, Vincenzo Mollace.
Am J Physiol Regul Integr Comp Physiol, 2013 Feb 08; 304(7). PMID: 23389111    Free PMC article.
Chemoprevention of Colon Cancer by iNOS-Selective Inhibitors.
Naveena B Janakiram, Chinthalapally V Rao.
For Immunopathol Dis Therap, 2012 Jan 01; 3(2). PMID: 23678395    Free PMC article.
Pea3 expression promotes the invasive and metastatic potential of colorectal carcinoma.
Aruz Mesci, Samira Taeb, +3 authors, Stanley K Liu.
World J Gastroenterol, 2014 Dec 18; 20(46). PMID: 25516649    Free PMC article.
The dual role of iNOS in cancer.
Federica Vannini, Khosrow Kashfi, Niharika Nath.
Redox Biol, 2015 Sep 04; 6. PMID: 26335399    Free PMC article.
Highly Cited. Review.
Inducible Nitric Oxide Synthase in the Carcinogenesis of Gastrointestinal Cancers.
Graciele Almeida de Oliveira, Robert Y S Cheng, +5 authors, David A Wink.
Antioxid Redox Signal, 2016 Nov 01; 26(18). PMID: 27494631    Free PMC article.
Cyclooxygenase-2 in Endometriosis.
Zhen-Zhen Lai, Hui-Li Yang, +8 authors, Ming-Qing Li.
Int J Biol Sci, 2019 Dec 20; 15(13). PMID: 31853218    Free PMC article.
Proline oxidase, a p53-induced gene, targets COX-2/PGE2 signaling to induce apoptosis and inhibit tumor growth in colorectal cancers.
Y Liu, G L Borchert, A Surazynski, J M Phang.
Oncogene, 2008 Sep 17; 27(53). PMID: 18794809    Free PMC article.
Hepatoprotective effect of Matricaria chamomilla aqueous extract against 1,2-Dimethylhydrazine-induced carcinogenic hepatic damage in mice.
Salima Shebbo, Manal El Joumaa, Rawan Kawach, Jamilah Borjac.
Heliyon, 2020 Jun 09; 6(6). PMID: 32509999    Free PMC article.
Nitric Oxide Mediates Insect Cellular Immunity via Phospholipase A2 Activation.
Md Sadekuzzaman, David Stanley, Yonggyun Kim.
J Innate Immun, 2017 Oct 17; 10(1). PMID: 29035888    Free PMC article.