This proposal is designed to understand the role played by epigenetic marks in normal and disease condition states. Chromosomal translocations that occur in various cancers can create fusion proteins, and these fusion proteins recruit histone deacetylases (HDACs) to repress the transcription of tumor suppressors and genes that are important for cellular differentiation. Pharmacological inhibitors of HDACs are in Phase I and Phase II clinical trials for various cancers, yet we still do not have a clear understanding of how broad-spectrum HDAC inhibitors (HDIs) kill cells or trigger differentiation. So far, studies to understand the action of histone deacetylase inhibitors have been limited to cell lines that lack critical cell cycle checkpoints. Therefore, to understand the physiological functions of HdacS, a HDAC enzyme that plays a very important role in nuclear hormone and other cell cycle signal transduction pathways, we created a conditional HdacS knockout mouse model. The preliminary data obtained after conditional deletion of HdacS in primary mouse embryo fibroblast cells gave us a vast amount of information on the vital roles of HdacS in cell cycle progression, DNA damage control and DNA repair. We found that HdacS causes DNA damage that in turn leads to apoptosis. This DNA damage is observed only in cycling cells and not in noncycling cells. Also, loss of HdacS causes genome instability in MEFs and hepatocellular carcinoma in mice. This proposal will further provide insight to the mechanistic functions for HdacS in genome stability maintenance using the mouse model system.
The specific aims are: 1) Elucidate the mechanism by which loss of HdacS affects DNA repair and cell cycle progression in vitro. 2) Examination of the in vivo requirements for HdacS in B-cell development. This work will not only provide a mechanistic basis for the action of histone deacetylase inhibitors but also has very important therapeutic benefits in treatment of various cancers. The proposed work to understand functions of HdacS will facilitate the design of better and more specific inhibitors to HDAC enzymes. This research will help us to provide the society with a better cure for cancer by designing more specific cancer drugs for clinical trials.
|Summers, Alyssa R; Fischer, Melissa A; Stengel, Kristy R et al. (2013) HDAC3 is essential for DNA replication in hematopoietic progenitor cells. J Clin Invest 123:3112-23|
|Wells, Christina E; Bhaskara, Srividya; Stengel, Kristy R et al. (2013) Inhibition of histone deacetylase 3 causes replication stress in cutaneous T cell lymphoma. PLoS One 8:e68915|
|Bhaskara, Srividya; Knutson, Sarah K; Jiang, Guochun et al. (2010) Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18:436-47|