Supplement to Support Research Training in HDAC11 and Cancer

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Project Summary The histone deacetylaces (HDACs) are originally discovered as critical epigenetic regulators implicated in a wide range of cancers. HDACs are most associated with their namesake deacetylase activity; they catalyze the removal of acetyl groups from lysine residues, which typically condenses chromatin and decreases expression of certain genes. However, there is increasing evidence that many HDACs exhibit other enzymatic functions such as defatty-acylase activity. Additionally, HDACs have been illustrated to interact with proteins other than histones; HDAC11 was previously illustrated to functionally interact with RNA splicing machinery. Thus, the enzymatic mechanism(s) and target proteins of HDACs are not fully understood. In supplement to our Parent R01 grant aimed at studying HDAC11 in lymphoma, we strive to investigate HDAC11 defatty-acylation in RNA splicing. Defatty-acylation can direct the localization of proteins, and HDAC11 functions more efficiently as a cytosolic defatty-acylase than as a nuclear deacetylase. Therefore, our aim is to identify HDAC11 proximate proteins in cancer cells, pinpoint the function of HDAC11 defatty-acylation, and identify alternatively spliced mRNAs in response to HDAC11 disruption. The proposed work will advance understanding of HDAC11 in cancer gene regulation, contribute to growing knowledge of diverse HDAC functions, and potentially open new avenues for HDAC dependent cancer therapies.