Abstract
The bromodomain protein BRD4 is involved in cell proliferation and cell cycle progression, primarily through its role in acetylated chromatin-dependent regulation of transcription at targeted loci. Here, we show that BRD4 is frequently downregulated by aberrant promoter hypermethylation in human colon cancer cell lines and primary tumors. Ectopic re-expression of BRD4 in these colon cancer cell lines markedly reduced in vivo tumor growth, suggesting a role of BRD4 in human colon cancer.
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Chiang CM (2009) Brd4 engagement from chromatin targeting to transcriptional regulation: selective contact with acetylated histone H3 and H4. F1000 Biol Rep 1:98
Dey A, Ellenberg J, Farina A, Coleman AE, Maruyama T, Sciortino S, Lippincott-Schwartz J, Ozato K (2000) A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition. Mol Cell Biol 20:6537–6549
Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K (2003) The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci USA 100:8758–8763
Dey A, Nishiyama A, Karpova T, McNally J, Ozato K (2009) Brd4 marks select genes on mitotic chromatin and directs postmitotic transcription. Mol Biol Cell 20:4899–4909
Hargreaves DC, Horng T, Medzhitov R (2009) Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138:129–145
Maruyama T, Farina A, Dey A, Cheong J, Bermudez VP, Tamura T, Sciortino S, Shuman J, Hurwitz J, Ozato K (2002) A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase. Mol Cell Biol 22:6509–6520
Houzelstein D, Bullock SL, Lynch DE, Grigorieva EF, Wilson VA, Beddington RS (2002) Growth and early postimplantation defects in mice deficient for the bromodomain-containing protein Brd4. Mol Cell Biol 22:3794–3802
You J, Li Q, Wu C, Kim J, Ottinger M, Howley PM (2009) Regulation of aurora B expression by the bromodomain protein Brd4. Mol Cell Biol 29:5094–5103
Mochizuki K, Nishiyama A, Jang MK, Dey A, Ghosh A, Tamura T, Natsume H, Yao H, Ozato K (2008) The bromodomain protein Brd4 stimulates G1 gene transcription and promotes progression to S phase. J Biol Chem 283:9040–9048
Nishiyama A, Dey A, Miyazaki J, Ozato K (2006) Brd4 is required for recovery from antimicrotubule drug-induced mitotic arrest: preservation of acetylated chromatin. Mol Biol Cell 17:814–823
French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA (2003) BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res 63:304–307
Crawford NP, Alsarraj J, Lukes L, Walker RC, Officewala JS, Yang HH, Lee MP, Ozato K, Hunter KW (2008) Bromodomain 4 activation predicts breast cancer survival. Proc Natl Acad Sci USA 105:6380–6385
Ropero S, Menendez JA, Vazquez-Martin A, Montero S, Cortes-Funes H, Colomer R (2004) Trastuzumab plus tamoxifen: anti-proliferative and molecular interactions in breast carcinoma. Breast Cancer Res Treat 86:125–137
Bibikova M, Lin Z, Zhou L, Chudin E, Garcia EW, Wu B, Doucet D, Thomas NJ, Wang Y, Vollmer E et al (2006) High-throughput DNA methylation profiling using universal bead arrays. Genome Res 16:383–393
Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K et al (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400
Acknowledgments
We thank OIB (FYCIT), M. Santirso, and C. Mark for editorial assistance. CH received support from FIS FI07/00380. AFF, RGU, RMU, and CM are supported by the IUOPA. This work was supported by grants from the Spanish Ministry of Health (PI061267, PS09/02454), the Spanish National Research Council (CSIC 200820I172 to MFF), and the Community of Asturias (FICYT IB09-106). The IUOPA is supported by the Obra Social Cajastur, Spain.
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The authors declare that they have no conflict of interests.
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Rodriguez, R.M., Huidobro, C., Urdinguio, R.G. et al. Aberrant epigenetic regulation of bromodomain Brd4 in human colon cancer. J Mol Med 90, 587–595 (2012). https://doi.org/10.1007/s00109-011-0837-0
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DOI: https://doi.org/10.1007/s00109-011-0837-0