Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP
| Autor: | David J. Meyers, Beth E. Zucconi, Philip A. Cole, Mingxuan Wu, Mitzi I. Kuroda, Jessica L. Makofske, Yousang Hwang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Protein domain Heterocyclic Compounds 4 or More Rings Biochemistry Article Piperidines Protein Domains Catalytic Domain Cell Line Tumor Gene expression Humans p300-CBP Transcription Factors Epigenetics Cell Proliferation Histone Acetyltransferases Regulation of gene expression Molecular Structure biology Chemistry Prostatic Neoplasms Drug Synergism Histone acetyltransferase Chromatin Cell biology Bromodomain Gene Expression Regulation Neoplastic Oxazepines Acetyltransferase PC-3 Cells biology.protein |
| Zdroj: | Biochemistry. 58:2133-2143 |
| ISSN: | 1520-4995 0006-2960 |
| Popis: | 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 chromatin binding 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: | OpenAIRE |
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