Abstract
15-Lipoxygenase-1 (15-LOX-1) is transcriptionally silenced in cancer cells, and its transcription reactivation (for example, through histone deacetylase inhibitors (HDACIs)) restores apoptosis to cancer cells. However, the exact mechanism underlying 15-LOX-1 transcription reactivation in cancer cells is still undefined. Therefore, we evaluated the critical mechanisms required for 15-LOX-1 transcription reactivation in colon cancer cells. Specific HDAC1 and HDAC2 inhibition activated 15-LOX-1 transcription. 15-LOX-1 transcription was repressed through transcription repressor complex recruitment in the region of −120 to −391 of the 15-LOX-1 promoter. The nucleosome remodeling and histone deacetylase (NuRD) repression complex was recruited to this region. Depsipeptide significantly reduced the recruitment of NuRD key components (for example, metastasis-associated protein 1 (MTA1) and HDAC1) to the 15-LOX-1 promoter before 15-LOX-1 transcriptional activation. Knock down of NuRD key components (for example, MTA1 and HDAC1) by small interfering RNA (siRNA) activated 15-LOX-1 transcription, as measured by luciferase reporter assays in stably transfected SW480 cells with the 15-LOX-1 promoter construct of the −391, but not the −120 region. Relative to expression in normal tissue, MTA1 expression in colorectal cancer mucosa from colorectal cancer patients was negatively related to 15-LOX-1 expression. Thus, our results show that NuRD contributes to 15-LOX-1 transcription suppression in colon cancer cells and that HDACIs can inhibit NuRD recruitment to a promoter to activate gene transcription, as in the case of 15-LOX-1.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ariel A, Serhan CN . (2007). Resolvins and protectins in the termination program of acute inflammation. Trends Immunol 28: 176–183.
Baer AN, Costello PB, Green FA . (1991). In vivo activation of an omega-6 oxygenase in human skin. Biochem Biophys Res Commun 180: 98–104.
Balasenthil S, Broaddus RR, Kumar R . (2006). Expression of metastasis-associated protein 1 (MTA1) in benign endometrium and endometrial adenocarcinomas. Hum Pathol 37: 656–661.
Bolden JE, Peart MJ, Johnstone RW . (2006). Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5: 769–784.
Brash AR, Boeglin WE, Chang MS . (1997). Discovery of a second 15S-lipoxygenase in humans. Proc Natl Acad Sci USA 94: 6148–6152.
Brehm A, Nielsen SJ, Miska EA, McCance DJ, Reid JL, Bannister AJ et al. (1999). The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. EMBO J 18: 2449–2458.
Chen GG, Xu H, Lee JF, Subramaniam M, Leung KL, Wang SH et al. (2003). 15-hydroxy-eicosatetraenoic acid arrests growth of colorectal cancer cells via a peroxisome proliferator-activated receptor gamma-dependent pathway. Int J Cancer 107: 837–843.
Conrad DJ, Lu M . (2000). Regulation of Human 12/15-Lipoxygenase by Stat6-Dependent Transcription. Am J Respir Cell Mol Biol 22: 226–234.
Deguchi A, Xing SW, Shureiqi I, Yang P, Newman RA, Lippman SM et al. (2005). Activation of protein kinase G up-regulates expression of 15-lipoxygenase-1 in human colon cancer cells. Cancer Res 65: 8442–8447.
Furumai R, Matsuyama A, Kobashi N, Lee KH, Nishiyama M, Nakajima H et al. (2002). FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res 62: 4916–4921.
Giannini R, Cavallini A . (2005). Expression analysis of a subset of coregulators and three nuclear receptors in human colorectal carcinoma. Anticancer Res 25: 4287–4292.
Gibbs JB . (2000). Mechanism-based target identification and drug discovery in cancer research. Science 287: 1969–1973.
Gleason MM, Rojas CJ, Learn KS, Perrone MH, Bilder GE . (1995). Characterization and inhibition of 15-lipoxygenase in human monocytes: comparison with soybean 15-lipoxygenase. Am J Physiol 268: C1301–C1307.
Hennig R, Kehl T, Noor S, Ding XZ, Rao SM, Bergmann F et al. (2007). 15-Lipoxygenase-1 Production is Lost in Pancreatic Cancer and Overexpression of the Gene Inhibits Tumor Cell Growth. Neoplasia 9: 917–926.
Heslin MJ, Hawkins A, Boedefeld W, Arnoletti JP, Frolov A, Soong R et al. (2005). Tumor-associated down-regulation of 15-lipoxygenase-1 is reversed by celecoxib in colorectal cancer. Ann Surg 241: 941–946, (Discussion 946–947).
Hsi LC, Xi X, Lotan R, Shureiqi I, Lippman SM . (2004). The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells. Cancer Res 64: 8778–8781.
Hsi LC, Xi X, Wu Y, Lippman SM . (2005). The methyltransferase inhibitor 5-aza-2-deoxycytidine induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells. Mol Cancer Ther 4: 1740–1746.
Huang BH, Laban M, Leung CHW, Lee L, Lee CK, Salto-Tellez M et al. (2005). Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1//WAF1 expression, independent of histone deacetylase 1. Cell Death Differ 12: 395–404.
Jiang WG, Watkins G, Douglas-Jones A, Mansel RE . (2006). Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. Prostaglandins Leukot Essent Fatty Acids 74: 235–245.
Kamitani H, Geller M, Eling T . (1998). Expression of 15-lipoxygenase by human colorectal carcinoma Caco-2 cells during apoptosis and cell differentiation. J Biol Chem 273: 21569–21577.
Kamitani H, Kameda H, Kelavkar UP, Eling TE . (2000). A GATA binding site is involved in the regulation of 15-lipoxygenase-1 expression in human colorectal carcinoma cell line, caco-2. FEBS Lett 467: 341–347.
Kamitani H, Taniura S, Ikawa H, Watanabe T, Kelavkar UP, Eling TE . (2001). Expression of 15-lipoxygenase-1 is regulated by histone acetylation in human colorectal carcinoma. Carcinogenesis 22: 187–191.
Li J, Wang J, Wang J, Nawaz Z, Liu JM, Qin J et al. (2000). Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J 19: 4342–4350.
Liu C, Xu D, Sjoberg J, Forsell P, Bjorkholm M, Claesson HE . (2004). Transcriptional regulation of 15-lipoxygenase expression by promoter methylation. Exp Cell Res 297: 61–67.
Manavathi B, Kumar R . (2007). Metastasis tumor antigens, an emerging family of multifaceted master coregulators. J Biol Chem 282: 1529–1533.
Marks PA, Richon VM, Miller T, Kelly WK . (2004). Histone Deacetylase Inhibitors. Adv Cancer Res 91: 137–168.
Nixon JB, Kim KS, Lamb PW, Bottone FG, Eling TE . (2004). 15-Lipoxygenase-1 has anti-tumorigenic effects in colorectal cancer. Prostaglandins Leukot Essent Fatty Acids 70: 7–15.
Ostareck DH, Ostareck-Lederer A, Wilm M, Thiele BJ, Mann M, Hentze MW . (1997). mRNA Silencing in Erythroid Differentiation: hnRNP K and hnRNP E1 Regulate 15-Lipoxygenase Translation from the 3' End. Cell 89: 597–606.
Serhan CN, Jain A, Marleau S, Clish C, Kantarci A, Behbehani B et al. (2003). Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators. J Immunol 171: 6856–6865.
Shankaranarayanan P, Chaitidis P, Kuhn H, Nigam S . (2001). Acetylation by histone acetyltransferase CREB-binding protein/p300 of STAT6 is required for transcriptional activation of the 15-lipoxygenase-1 gene. J Biol Chem 276: 42753–42760.
Sharma D, Saxena NK, Davidson NE, Vertino PM . (2006). Restoration of tamoxifen sensitivity in estrogen receptor-negative breast cancer cells: tamoxifen-bound reactivated ER recruits distinctive corepressor complexes. Cancer Res 66: 6370–6378.
Shureiqi I, Chen D, Lee JJ, Yang P, Newman RA, Brenner DE et al. (2000a). 15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells. J Natl Cancer Inst 92: 1136–1142.
Shureiqi I, Chen D, Lotan R, Yang P, Newman RA, Fischer SM et al. (2000b). 15-Lipoxygenase-1 mediates nonsteroidal anti-inflammatory drug-induced apoptosis independently of cyclooxygenase-2 in colon cancer cells. Cancer Res 60: 6846–6850.
Shureiqi I, Jiang W, Fischer SM, Xu X, Chen D, Lee JJ et al. (2002). GATA-6 transcriptional regulation of 15-lipoxygenase-1 during NSAID-induced apoptosis in colorectal cancer cells. Cancer Res 62: 1178–1183.
Shureiqi I, Jiang W, Zuo X, Wu Y, Stimmel JB, Leesnitzer LM et al. (2003). The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-delta to induce apoptosis in colorectal cancer cells. Proc Natl Acad Sci USA 100: 9968–9973.
Shureiqi I, Wojno KJ, Poore JA, Reddy RG, Moussalli MJ, Spindler SA et al. (1999). Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers. Carcinogenesis 20: 1985–1995.
Shureiqi I, Wu Y, Chen D, Yang XL, Guan B, Morris JS et al. (2005). The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis. Cancer Res 65: 11486–11492.
Shureiqi I, Xu X, Chen D, Lotan R, Morris JS, Fischer SM et al. (2001). Nonsteroidal anti-inflammatory drugs induce apoptosis in esophageal cancer cells by restoring 15-lipoxygenase-1 expression. Cancer Res 61: 4879–4884.
Shureiqi I, Zuo X, Broaddus R, Wu Y, Guan B, Morris JS et al. (2007). The transcription factor GATA-6 is overexpressed in vivo and contributes to silencing 15-LOX-1 in vitro in human colon cancer. FASEB J 21: 743–753.
Takamitsu S, Kiyomu F, Kazuhiro Y, Hideo S, Tomonori S, Hitoshi O et al. (2006). Peritoneal metastasis inhibition by linoleic acid with activation of PPARã in human gastrointestinal cancer cells. Virchows Archiv 448: 422–427.
Takata S, Matsubara M, Allen PG, Janmey PA, Serhan CN, Brady HR . (1994). Remodeling of neutrophil phospholipids with 15(S)- hydroxyeicosatetraenoic acid inhibits leukotriene B4-induced neutrophil migration across endothelium. J Clin Invest 93: 499–508.
Wu J, Xia HH, Tu SP, Fan DM, Lin MC, Kung HF et al. (2003). 15-Lipoxygenase-1 mediates cyclooxygenase-2 inhibitor-induced apoptosis in gastric cancer. Carcinogenesis 24: 243–247.
Wu Y, Fang B, Yang XQ, Wang L, Chen D, Krasnykh V et al. (2008). Therapeutic molecular targeting of 15-lipoxygenase-1 in colon cancer. Mol Ther 16: 886–892.
Xue Y, Wong J, Moreno GT, Young MK, Cote J, Wang W . (1998). NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell 2: 851–861.
Zhang C, Richon V, Ni X, Talpur R, Duvic M . (2005a). Selective induction of apoptosis by Histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. J Investig Dermatol 125: 1045–1052.
Zhang X-y, DeSalle LM, Patel JH, Capobianco AJ, Yu D, Thomas-Tikhonenko A et al. (2005b). Metastasis-associated protein 1 (MTA1) is an essential downstream effector of the c-MYC oncoprotein. PNAS 102: 13968–13973.
Zhu P, Martin E, Mengwasser J, Schlag P, Janssen KP, Gottlicher M . (2004). Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell 5: 455–463.
Zuo X, Shen L, Issa J-P, Moy O, Morris JS, Lippman SM et al. (2008). 15-Lipoxygenase-1 transcriptional silencing by DNA methyltransferase-1 independently of DNA methylation. FASEB J 22: 1981–1992.
Zuo X, Wu Y, Morris JS, Stimmel JB, Leesnitzer LM, Fischer SM et al. (2006). Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity. Oncogene 25: 1225–1241.
Acknowledgements
This study was supported by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services R01 grants CA106577 and CA104278; the Caroline Wiess Law Endowment for Cancer Prevention; the Jerry and Maury Rubenstein Foundation and the National Colorectal Cancer Research Alliance. We thank Merck and Company Inc., Gloucester Pharmaceuticals and the National Cancer Institute for providing SAHA and depsipeptide. We also thank Ann M. Sutton, Department of Scientific Publications, the University of Texas M D Anderson Cancer Center, for editing the manuscript.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
Supplementary information
Rights and permissions
About this article
Cite this article
Zuo, X., Morris, J., Broaddus, R. et al. 15-LOX-1 transcription suppression through the NuRD complex in colon cancer cells. Oncogene 28, 1496–1505 (2009). https://doi.org/10.1038/onc.2008.494
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2008.494
Keywords
This article is cited by
-
GFI1 tethers the NuRD complex to open and transcriptionally active chromatin in myeloid progenitors
Communications Biology (2021)
-
Molecular functions and significance of the MTA family in hormone-independent cancer
Cancer and Metastasis Reviews (2014)
-
Induction of apoptosis by Trichostatin A in human breast cancer cell lines: involvement of 15-Lox-1
Tumor Biology (2013)