Histone deacetylase inhibition leads to dose-dependent suppression of oncogene-associated super-enhancers


In cancer cells, decreased histone acetylation leads to gene expression patterns that drive oncogenic processes. Histone deacetylase (HDAC) inhibitors are therefore used as therapeutics to selectively kill cancer cells. The complex processes by which these chromatin‐remodeling agents affect gene expression and ultimately cell fate are still not entirely understood. The Liu group seeks to characterize the mechanisms of the HDAC inhibitor largazole by using epigenomic and transcriptomic studies to compare its effects on transformed and non‐transformed cells at different doses. From broad chromatin immunoprecipitation sequencing and RNA sequencing, we observed that largazole has a striking effect on super‐enhancer regions and the genes associated with them. Largazole decreases the accumulation of RNA polymerase II at super‐enhancer elements and limits the transcription of genes under the regulation of those super‐enhancers. Largazole also alters the expression of many genes by decreasing the histone acetylation of poised distal enhancers in a dose‐dependent manner. Many of these genes are transcriptionally upregulated after treatment, as is canonically associated with an increased histone acetylation profile, but some transcripts are repressed. These insights into the epigenetic reprogramming that drives oncogenic processes provide fundamental information about tumorigenesis and could potentially serve as a foundation for the development of further oncology therapies.

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