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AZD5153, a bivalent BRD4 inhibitor, inhibits hepatocellular cancer growth by modulating the HCC transcriptome through repression of critical oncogenes through dissociation of BRD4 from the enhancer/promoter regions of critical genes

ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related death worldwide because of late stage detection when curative therapy is not available. The bromodomain and extraterminal (BET) protein BRD4 activates gene expression by interacting with histone H3K27-acetylated (H3K27Ac) chromatin. AZD5153 is an orally bioavailable, potent, bivalent BRD4 inhibitor, currently undergoing clinical trials in lymphoma and ovarian cancer patients. Here, we studied therapeutic potential of AZD5153 against HCC and elucidated the underlying mechanism. In conclusion, our results in preclinical models indicate that the combined effect of AZD5153 could be a novel targeted therapy for HCC and provides rationale for clinical trials of an AZD5153-FK866 combination as an effective and attractive strategy to treat this deadly disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE172186 | GEO | 2022/01/13

REPOSITORIES: GEO

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Project description:DNA damage activates a complex signaling network in cells that blocks cell cycle progression, recruits factors involved in DNA repair, and/or triggers programs that control senescence or programmed cell death. Alterations in chromatin structure are known to be important for the initiation and propagation of the DNA damage response, although the molecular details are unclear. We investigated the role of chromatin structure in the DNA damage response by monitoring multiple timedependent checkpoint signaling and response events with a high-content multiplex image-based RNAi screen of chromatin modifying and interacting genes. We discovered that Brd4, a double bromodomain-containing protein, functions as an endogenous inhibitor of DNA damage signaling by binding to acetylated histones at sites of open chromatin and altering chromatin accessibility. Loss of Brd4 or disruption of acetyl-lysine binding results in an increase in both the number and size of radiation-induced !H2AX nuclear foci while overexpression of a Brd4 splice isoform completely suppresses !H2AX formation, despite equivalent double strand break formation. Brd4 knock-down cells displayed altered chromatin structure, prolonged cell cycle checkpoint arrest and enhanced survival after irradiation, while overexpression of Brd4 isoform B results in enhanced radiationinduced lethality. Brd4 is the target of the t(15;19) chromosomal translocation in a rare form of cancer, NUT Midline Carcinoma. Acetyl lysine-bromodomain interactions of the Brd4-NUT fusion protein suppresses !H2AX foci in discrete nuclear compartments, rendering cells more radiosensitive, mimicking overexpression of Brd4 isoform B. NUT Midline Carcinoma is sensitive to radiotherapy, however tumor material from this rare cancer is scarce. We therefore investigated Brd4 expression in another human cancer commonly treated with radiotherapy, glioblastoma multiforme, and found that expression of Brd4 isoform B correlated specifically with treatment response to radiotherapy. These data implicate Brd4 as an endogenous insulator of DNA damage signaling through recognition of epigenetic modifications in chromatin and suggest that expression of the Brd4 in human cancer can modulate the clinical response to DNA-damaging cancer therapy. Two replicates each of U2OS cells expressing either Brd4 shRNA or a control shRNA

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AZD5153, a bivalent BRD4 inhibitor, inhibits hepatocellular cancer growth by modulating the HCC transcriptome through repression of critical oncogenes through dissociation of BRD4 from the enhancer/promoter regions of critical genes

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