Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP.

Autor:	Zucconi BE; Division of Genetics, Department of Medicine , Brigham and Women's Hospital , Boston , Massachusetts 02115 , United States.; Department of Biological Chemistry and Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02115 , United States., Makofske JL; Division of Genetics, Department of Medicine , Brigham and Women's Hospital , Boston , Massachusetts 02115 , United States.; Department of Genetics , Harvard Medical School , Boston , Massachusetts 02115 , United States., Meyers DJ; Department of Pharmacology and Molecular Sciences , Johns Hopkins School of Medicine , Baltimore , Maryland 21205 , United States., Hwang Y; Department of Pharmacology and Molecular Sciences , Johns Hopkins School of Medicine , Baltimore , Maryland 21205 , United States., Wu M; Division of Genetics, Department of Medicine , Brigham and Women's Hospital , Boston , Massachusetts 02115 , United States.; Department of Biological Chemistry and Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02115 , United States., Kuroda MI; Division of Genetics, Department of Medicine , Brigham and Women's Hospital , Boston , Massachusetts 02115 , United States.; Department of Genetics , Harvard Medical School , Boston , Massachusetts 02115 , United States., Cole PA; Division of Genetics, Department of Medicine , Brigham and Women's Hospital , Boston , Massachusetts 02115 , United States.; Department of Biological Chemistry and Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
Jazyk:	angličtina
Zdroj:	Biochemistry [Biochemistry] 2019 Apr 23; Vol. 58 (16), pp. 2133-2143. Date of Electronic Publication: 2019 Apr 11.
DOI:	10.1021/acs.biochem.9b00160
Abstrakt:	p300 and CBP are highly related histone acetyltransferase (HAT) enzymes that regulate gene expression, and their dysregulation has been linked to cancer and other diseases. p300/CBP is composed of a number of domains including a HAT domain, which is inhibited by the small molecule A-485, and an acetyl-lysine binding bromodomain, which was recently found to be selectively antagonized by the small molecule I-CBP112. Here we show that the combination of I-CBP112 and A-485 can synergize to inhibit prostate cancer cell proliferation. We find that the combination confers a dramatic reduction in p300 chromatin occupancy compared to the individual effects of blocking either domain alone. Accompanying this loss of p300 on chromatin, combination treatment leads to the reduction of specific mRNAs including androgen-dependent and pro-oncogenic prostate genes such as KLK3 (PSA) and c-Myc. Consistent with p300 directly affecting gene expression, mRNAs that are significantly reduced by combination treatment also exhibit a strong reduction in p300 chromatin occupancy at their gene promoters. The relatively few mRNAs that are up-regulated upon combination treatment show no correlation with p300 occupancy. These studies provide support for the pharmacologic advantage of concurrent targeting of two domains within one key epigenetic modification enzyme.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu