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.
Highlights
IntroductionHistone acetylation changes chromatin organization and largely affects gene expression regulation
Histone acetylation changes chromatin organization and largely affects gene expression regulation.The chromatin acetylation status is regulated by three main protein families
Since they have a crucial role in transcription regulation, both Histone DeACetylase (HDACs) and Bromodomain and Extraterminal domain (BET) proteins have been considered as potential targets for anticancer strategies
Summary
Histone acetylation changes chromatin organization and largely affects gene expression regulation. They add acetyl groups to the lysine residues on target proteins including histones, leading to loosening of chromatin conformation and promoting transcription. They remove acetyl groups from histone and non-histone proteins returning chromatin to a less accessible conformation and restraining transcription. Cancer development and progression heavily rely on gene expression reprogramming [3,4]. Since they have a crucial role in transcription regulation, both HDAC and BET proteins have been considered as potential targets for anticancer strategies. We aim to summarize the employment of these drugs in the cure of cancer, discussing their potential interplay with other drugs
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