CREBBP/EP300 bromodomains are critical to sustain the GATA1/MYC regulatory axis in proliferation

Abstract

BackgroundThe reported antitumor activity of the BET family bromodomain inhibitors has prompted the development of inhibitors against other bromodomains. However, the human genome encodes more than 60 different bromodomains and most of them remain unexplored.ResultsWe report that the bromodomains of the histone acetyltransferases CREBBP/EP300 are critical to sustain the proliferation of human leukemia and lymphoma cell lines. EP300 is very abundant at super-enhancers in K562 and is coincident with sites of GATA1 and MYC occupancy. In accordance, CREBBP/EP300 bromodomain inhibitors interfere with GATA1- and MYC-driven transcription, causing the accumulation of cells in the G0/G1 phase of the cell cycle. The CREBBP/CBP30 bromodomain inhibitor CBP30 displaces CREBBP and EP300 from GATA1 and MYC binding sites at enhancers, resulting in a decrease in the levels of histone acetylation at these regulatory regions and consequently reduced gene expression of critical genes controlled by these transcription factors.ConclusionsOur data shows that inhibition of CREBBP/EP300 bromodomains can interfere with oncogene-driven transcriptional programs in cancer cells and consequently hold therapeutic potential.Electronic supplementary materialThe online version of this article (10.1186/s13072-018-0197-x) contains supplementary material, which is available to authorized users.

Therapeutic potential of TAF1 bromodomains for cancer treatment

“…Importantly, JQ1 also causes an increase in the percentage of cells in G0/1 that correlates with the overlap in transcriptional changes caused by JQ1 and the TAF1 knock down. Importantly, we have previously described that CBP30 also increases the number of cells in G0/1 in K562 [8] which also correlates with the overlap in transcriptional responses to CBP30 and TAF1 knock down. In Importantly, the analysis of enrichment in genomic features revealed that even though BAY-299 and the TAF1 knock down downregulated the expression of genes occupied by TAF1, BAY-299 specifically downregulated the expression of genes that in addition have very high levels of acetylation at their promoters.…”

“…We next investigated which transcriptional pathways could be affected by the TAF1 knock down and BAY-299 treatment. Our previous work showed that CBP30 downregulates both the GATA1 and MYC-dependent transcriptional signature in K562 [8]. Like CBP30, sh670 and BAY-299 downregulated genes typically upregulated by MYC and targets of GATA1 in K562 ( Figure 3A).…”

“…Non target gRNAs sequences were previously described [12]. gRNAs against BRD4 were previously described [8]. gRNAs were cloned into pKLV-U6gRNA(BbsI)-PGKpuro2ABFP (Addgene plasmid # 50946).…”

CREBBP/EP300 Bromodomain Inhibition Affects the Proliferation of AR-Positive Breast Cancer Cell Lines

“…Our previous work has demonstrated that CREBBP/EP300 bromodomain inhibitors are able to displace CREBBP and EP300 from acetylated genomic regions resulting in lower levels of histone acetylation at these sites (16). Therefore, we asked whether CREBBP/EP300 bromodomain inhibitors could be reducing the levels of H3K27ac at AR-binding sites located in SEs (see Supplementary Fig.…”

“…Prompted by the preclinical success of BET bromodomains inhibitors, dual inhibitors of the bromodomains of CREBBP and EP300 have been recently developed (9)(10)(11)(12)(13)(14)(15). These inhibitors mediate several biological responses including antiproliferative effects in hematologic cancer cell lines, such as leukemia (11,13,16) and multiple myeloma (17) cell lines, and AR-positive prostate cancer cell lines (15). Moreover, EP300/CREBBP bromodomain inhibitors interfere with important oncogenic transcription programs driven by transcription factors such as MYC, IRF4, GATA1, and AR (13,(15)(16)(17).…”