Determining the role of BRD4 in the Cellular Response to Histone Deacetylase Inhibitors (2016)

Undergraduate: Ian Tsun

Faculty Advisor: Brian Strahl
Department: Chemistry

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Histone post-translational modifications (PTMs) promote chromatin remodeling and regulate chromatin-related activities such as transcription and DNA replication. Histone acetylation is associated with ¿¿¿loosening¿¿¿ the chromatin structure and acts as a docking site for the recruitment of nuclear proteins to specific locations in the genome. Histone deacetylase (HDAC) inhibitors are a novel class of anti-cancer drugs that prevents the removal of histone acetylation thereby increasing global levels of acetylation. A massive increase in histone acetylation alters gene expression and impairs cancer cell growth. Currently there are four FDA-approved HDAC inhibitors used for cancer therapies. However, much is still unknown about the mechanisms through which HDAC inhibitors regulate gene expression and inhibit cell growth. BRD4 is a member of the super elongation complex that has been linked to the activation of several oncogenes. BRD4 is recruited to chromatin by histone acetylation, suggesting that BRD4 may regulate the gene expression changes that occur after HDAC inhibitor treatment. In order to test this hypothesis, BRD4 levels were knocked down by shRNA or overexpressed and gene expression changes in response to HDAC inhibitors was measured by PCR. Current studies are also focused measuring cell growth in response to HDAC inhibitors when BRD4 is knocked down or overexpressed, leading to a better understanding of the mechanism through which HDAC inhibitors affect cells.