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

08:00 EDT 29th March 2019 | BioPortfolio

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

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.


Journal Details

This article was published in the following journal.

Name: Biochemistry
ISSN: 1520-4995


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Medical and Biotech [MESH] Definitions

A member of the p300-CBP transcription factors that was originally identified as a binding partner for ADENOVIRUS E1A PROTEINS.

An enzyme that catalyzes the transfer of acetyl groups from ACETYL-COA to arylamines. It can also catalyze acetyl transfer between arylamines without COENZYME A and has a wide specificity for aromatic amines, including SEROTONIN. However, arylamine N-acetyltransferase should not be confused with the enzyme ARYLALKYLAMINE N-ACETYLTRANSFERASE which is also referred to as SEROTONIN ACETYLTRANSFERASE.

An acetyltransferase with specificity towards the amine group of aromatic alkylamines (arylalkylamines) such as SEROTONIN. This enzyme is also referred to as serotonin acetylase despite the fact that serotonin acetylation can also occur through the action of broad specificity acetyltransferases such as ARYLAMINE N-ACETYLTRANSFERASE.

A retinoblastoma-binding protein that is found as a subunit of protein complexes involved in the acetylation of newly synthesized histones. Although initially discovered as a retinoblastoma binding protein, it also has an affinity for core HISTONES and plays a role in recruiting core histone proteins to the active site of the acetyltransferase enzyme complexes.

A late-appearing component of the event-related potential. P300 stands for a positive deflection in the event-related voltage potential at 300 millisecond poststimulus. Its amplitude increases with unpredictable, unlikely, or highly significant stimuli and thereby constitutes an index of mental activity. (From Campbell, Psychiatric Dictionary, 6th ed)

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