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Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells
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Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy

Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy
Author to whom correspondence should be addressed.
Cancers 2019, 11(3), 304;
Received: 24 January 2019 / Revised: 18 February 2019 / Accepted: 26 February 2019 / Published: 5 March 2019
(This article belongs to the Collection Histone Modification in Cancer)
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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. View Full-Text
Keywords: epigenetic drugs; histone modifications; BET protein; HDAC; combination therapy; cancer epigenetic drugs; histone modifications; BET protein; HDAC; combination therapy; cancer

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Manzotti, G.; Ciarrocchi, A.; Sancisi, V. Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy. Cancers 2019, 11, 304.

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