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Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy.

ABSTRACT: Histone DeACetylases (HDACs) are enzymes that remove acetyl groups from histones and other proteins, regulating the expression of target genes. Pharmacological inhibition of these enzymes re-shapes chromatin acetylation status, confusing boundaries between transcriptionally active and quiescent chromatin. This results in reinducing expression of silent genes while repressing highly transcribed genes. Bromodomain and Extraterminal domain (BET) proteins are readers of acetylated chromatin status and accumulate on transcriptionally active regulatory elements where they serve as scaffold for the building of transcription-promoting complexes. The expression of many well-known oncogenes relies on BET proteins function, indicating BET inhibition as a strategy to counteract their activity. BETi and HDACi share many common targets and affect similar cellular processes to the point that combined inhibition of both these classes of proteins is regarded as a strategy to improve the effectiveness of these drugs in cancer. In this work, we aim to discuss the molecular basis of the interplay between HDAC and BET proteins, pointing at chromatin acetylation as a crucial node of their functional interaction. We will also describe the state of the art of their dual inhibition in cancer therapy. Finally, starting from their mechanism of action we will provide a speculative perspective on how these drugs may be employed in combination with standard therapies to improve effectiveness and/or overcome resistance.

SUBMITTER: Manzotti G

PROVIDER: S-EPMC6468908 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy.

Manzotti Gloria G Ciarrocchi Alessia A Sancisi Valentina V

Cancers 20190305 3

Histone DeACetylases (HDACs) are enzymes that remove acetyl groups from histones and other proteins, regulating the expression of target genes. Pharmacological inhibition of these enzymes re-shapes chromatin acetylation status, confusing boundaries between transcriptionally active and quiescent chromatin. This results in reinducing expression of silent genes while repressing highly transcribed genes. Bromodomain and Extraterminal domain (BET) proteins are readers of acetylated chromatin status a ...[more]

PMID: 30841549

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Project description:BackgroundNew efficient therapies for urothelial carcinoma (UC) are urgently required. Small-molecule drugs targeting chromatin regulators are reasonable candidates because these regulators are frequently mutated or deregulated in UC. Indeed, in previous work, Romidepsin, which targets class I histone deacetylases (HDAC), efficiently killed UC cells, but did not elicit canonical apoptosis and affected benign urothelial cells indiscriminately. Combinations of HDAC inhibitors with JQ1, an inhibitor of bromodomain-containing acetylation reader proteins like BRD4, which promote especially the transcription of pro-tumorigenic genes, have shown efficacy in several tumor types. We therefore investigated the effects of combined Romidepsin and JQ1 treatment on UC and benign urothelial control cells.ResultsJQ1 alone induced cell cycle arrest, but only limited apoptosis in eight UC cell lines with strongly varying IC50 values between 0.18 and 10 μM. Comparable effects were achieved by siRNA-mediated knockdown of BRD4. Romidepsin and JQ1 acted in a synergistic manner across all UC cell lines, efficiently inhibiting cell cycle progression, suppressing clonogenic growth, and inducing caspase-dependent apoptosis. Benign control cells were growth-arrested without apoptosis induction, but retained long-term proliferation capacity. In UC cells, anti-apoptotic and oncogenic factors Survivin, BCL-2, BCL-XL, c-MYC, EZH2 and SKP2 were consistently downregulated by the drug combination and AKT phosphorylation was diminished. Around the transcriptional start sites of these genes, the drug combination enhanced H3K27 acetylation, but decreased H3K4 trimethylation. The cell cycle inhibitor CDKN1C/p57KIP2 was dramatically induced at mRNA and protein levels. However, Cas9-mediated CDKN1C/p57KIP2 knockout did not rescue UC cells from apoptosis.ConclusionOur results demonstrate significant synergistic effects on induction of apoptosis in UC cells by the combination treatment with JQ1 and Romidepsin, but only minor effects in benign cells. Thus, this study established a promising new small-molecule combination therapy approach for UC.

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Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy.

Publications

Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy.

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