Abstract
Inhibitors that prevent the binding of bromodomains to acetylated histones hold therapeutic potential. However, the effects of targeting most of the 60 different bromodomains found in the human proteome remain unexplored. Here, we investigate the molecular mechanisms responsible for the antiproliferative properties of CREBBP/EP300 bromodomain inhibition in ER-negative breast cancer cell lines. We show using genetic and chemical approaches that CREBBP/EP300 bromodomains are critical to support the proliferation of the triple-negative breast cancer cell line MDA-MB-453. Analysis of the transcriptional pathways affected by CREBBP/EP300 bromodomain inhibitors reveals that the expression of genes associated with super-enhancers is downregulated, which in turn are occupied by very high levels of androgen receptor (AR) in MDA-MB-453 cells. Treatment of MDA-MB-453 with CREBBP/EP300 bromodomain inhibitors downregulates the expression of an AR-dependent signature distinctive of breast cancer tumors that express AR and causes a decrease in H3K27ac levels at AR-binding sites. In accordance, in prostate cancer cell lines that express AR CREBBP/EP300 bromodomain inhibitors downregulate the expression of genes bound by AR and associated with super-enhancers. In summary, we report that triple-negative breast cancer cell lines that express AR are particularly sensitive to CREBBP/EP300 bromodomain inhibitors and consequently these inhibitors hold potential to treat this type of cancer. IMPLICATIONS: AR-dependent cancer cell lines are sensitive to CREBBP/EP300 bromodomain inhibitors.
Highlights
Bromodomain-containing proteins can act as effectors of histone acetylation as they are able to recognize acetylated residues in histone tails [1]
Despite the fact that CBP30 and I-CBP112 have been described to have good selectivity over other bromodomains [11, 31] we found pertinent to confirm the involvement of EP300 and CREBBP bromodomains in the proliferation of MDA-MB453 cells using a recently described CRISPR-Cas9 genome editing approach to evaluate the relevance of protein domains in proliferation [32, 33]
Our CRISPR-Cas9 approach confirms that the bromodomains of CREBBP and EP300 are relevant to sustain the proliferation of MDA-MB-453
Summary
Bromodomain-containing proteins can act as effectors of histone acetylation as they are able to recognize acetylated residues in histone tails [1]. It has been shown that inhibitors that block the interaction of bromodomains with acetylated residues have therapeutic potential [2]. Inhibitors of the bromo and extraterminal domain (BET) family of bromodomain-containing proteins have been described to mediate important antiproliferative effects in cancer cell lines and are currently being tested in clinical trials [3]. The mechanism of action of BET inhibitors consist on blocking the expression of oncogenes that are associated with enhancers with very high levels of histone acetylation known as super-enhancers (SE) and, in this way, inhibit oncogene-driven proliferation of cancer cells [4].
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