BET Domain Co-regulators in Obesity, Inflammation and Cancer

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2012 Jun 23

PMID 22722403

Citations 364

Authors

Anna C Belkina

Gerald V Denis

Affiliations

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Abstract

The bromodomain is a highly conserved motif of 110 amino acids that is bundled into four anti-parallel α-helices and found in proteins that interact with chromatin, such as transcription factors, histone acetylases and nucleosome remodelling complexes. Bromodomain proteins are chromatin 'readers'; they recruit chromatin-regulating enzymes, including 'writers' and 'erasers' of histone modification, to target promoters and to regulate gene expression. Conventional wisdom held that complexes involved in chromatin dynamics are not 'druggable' targets. However, small molecules that inhibit bromodomain and extraterminal (BET) proteins have been described. We examine these developments and discuss the implications for small molecule epigenetic targeting of chromatin networks in cancer.

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References

Kanno T, Kanno Y, Siegel R, Jang M, Lenardo M, Ozato K . Selective recognition of acetylated histones by bromodomain proteins visualized in living cells. Mol Cell. 2004; 13(1):33-43. DOI: 10.1016/s1097-2765(03)00482-9. View

Wang E, Zou S, Tjian R . TAFII250-dependent transcription of cyclin A is directed by ATF activator proteins. Genes Dev. 1997; 11(20):2658-69. PMC: 316605. DOI: 10.1101/gad.11.20.2658. View

Horn P, Peterson C . The bromodomain: a regulator of ATP-dependent chromatin remodeling?. Front Biosci. 2001; 6:D1019-23. DOI: 10.2741/horn. View

Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K . The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci U S A. 2003; 100(15):8758-63. PMC: 166386. DOI: 10.1073/pnas.1433065100. View

French C, Ramirez C, Kolmakova J, Hickman T, Cameron M, Thyne M . BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene. 2007; 27(15):2237-42. DOI: 10.1038/sj.onc.1210852. View

Zhang L, Deng T, Li X, Liu H, Zhou H, Ma J . microRNA-141 is involved in a nasopharyngeal carcinoma-related genes network. Carcinogenesis. 2010; 31(4):559-66. DOI: 10.1093/carcin/bgp335. View

Kuras L, Borggrefe T, Kornberg R . Association of the Mediator complex with enhancers of active genes. Proc Natl Acad Sci U S A. 2003; 100(24):13887-91. PMC: 283516. DOI: 10.1073/pnas.2036346100. View

Burns L, Peterson C . The yeast SWI-SNF complex facilitates binding of a transcriptional activator to nucleosomal sites in vivo. Mol Cell Biol. 1997; 17(8):4811-9. PMC: 232333. DOI: 10.1128/MCB.17.8.4811. View

Bonora E, Willeit J, Kiechl S, Oberhollenzer F, Egger G, Bonadonna R . U-shaped and J-shaped relationships between serum insulin and coronary heart disease in the general population. The Bruneck Study. Diabetes Care. 1998; 21(2):221-30. DOI: 10.2337/diacare.21.2.221. View

10.

McPhillips M, Oliveira J, Spindler J, Mitra R, McBride A . Brd4 is required for e2-mediated transcriptional activation but not genome partitioning of all papillomaviruses. J Virol. 2006; 80(19):9530-43. PMC: 1617221. DOI: 10.1128/JVI.01105-06. View

11.

Chung C, Dean A, Woolven J, Bamborough P . Fragment-based discovery of bromodomain inhibitors part 1: inhibitor binding modes and implications for lead discovery. J Med Chem. 2011; 55(2):576-86. DOI: 10.1021/jm201320w. View

12.

Tamkun J, Deuring R, Scott M, Kissinger M, Pattatucci A, Kaufman T . brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell. 1992; 68(3):561-72. DOI: 10.1016/0092-8674(92)90191-e. View

13.

Maruyama T, Farina A, Dey A, Cheong J, Bermudez V, Tamura T . A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase. Mol Cell Biol. 2002; 22(18):6509-20. PMC: 135621. DOI: 10.1128/MCB.22.18.6509-6520.2002. View

14.

Kubonishi I, Takehara N, Iwata J, Sonobe H, Ohtsuki Y, Abe T . Novel t(15;19)(q15;p13) chromosome abnormality in a thymic carcinoma. Cancer Res. 1991; 51(12):3327-8. View

15.

Stiegler P, De Luca A, Bagella L, Giordano A . The COOH-terminal region of pRb2/p130 binds to histone deacetylase 1 (HDAC1), enhancing transcriptional repression of the E2F-dependent cyclin A promoter. Cancer Res. 1998; 58(22):5049-52. View

16.

Mueller D, Bach C, Zeisig D, Garcia-Cuellar M, Monroe S, Sreekumar A . A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood. 2007; 110(13):4445-54. PMC: 2234781. DOI: 10.1182/blood-2007-05-090514. View

17.

Delmore J, Issa G, Lemieux M, Rahl P, Shi J, Jacobs H . BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011; 146(6):904-17. PMC: 3187920. DOI: 10.1016/j.cell.2011.08.017. View

18.

Yang Z, Yik J, Chen R, He N, Jang M, Ozato K . Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell. 2005; 19(4):535-45. DOI: 10.1016/j.molcel.2005.06.029. View

19.

Chua P, Roeder G . Bdf1, a yeast chromosomal protein required for sporulation. Mol Cell Biol. 1995; 15(7):3685-96. PMC: 230606. DOI: 10.1128/MCB.15.7.3685. View

20.

Jacobson R, Ladurner A, King D, Tjian R . Structure and function of a human TAFII250 double bromodomain module. Science. 2000; 288(5470):1422-5. DOI: 10.1126/science.288.5470.1422. View