Histone deacetylases regulate chromatin structure, transcription, replication, and DNA repair/recombination. Because of these key roles in cell cycle control, HDACs have become an important target for therapeutic intervention in a variety of tumors and the first Histone Deacetylase Inhibitor (HDI) has received FDA approval. Histone deacetylase 3 (Hdac3) is a key regulator of chromatin structure and gene expression and our preliminary data suggests that it may be a central target of HDIs. Because of the multi-faceted action of histone deacetylases, it has been difficult to pin down how inhibiting these enzymes acts to kill cancer cells while sparing surrounding normal tissues. Therefore, we set out to understand the action of Hdac3 by engineering mice containing a """"""""floxed"""""""" Hdac3. Deletion of Hdac3 in the germ line caused early embryonic lethality. Moreover, Hdac3 deletion was even lethal to murine embryonic fibroblasts in vitro. Although we approached this analysis with a """"""""transcription bias"""""""", gene expression array analysis failed to identify the induction of a gene expression pattern that might explain this apoptosis. By contrast, careful analysis of the cell cycle indicated that apoptosis required S phase progression and that S phase was slowed. Surprisingly, the S phase DNA damage checkpoint was activated in the absence of Hdac3. This observation, coupled with data linking Hdac3 to DNA repair, led us to the discovery that loss of Hdac3 caused DNA damage that was most likely due to inefficient repair of the DNA double strand breaks that occur at stalled DNA replication forks. We have now begun to translate this information to the in vivo requirements for Hdac3 in adult mice. Removal of Hdac3 in the mouse liver caused a phenotype similar to non-alcoholic fatty liver disease, which was likely due to de- regulated nuclear hormone receptor functions. Most importantly, consistent with defects in DNA repair and genomic instability, the liver-specific deletion of Hdac3 caused a 100% penetrant hepatocellular carcinoma with a mean time to HCC of 10.2 months. We hypothesize that Hdac3 is required for efficient DNA repair and that loss of Hdac3 causes genomic instability that leads to cancer development, but that we can take advantage of these defects in DNA repair to treat cancer. This proposal will further define the mechanisms by which inactivation of Hdac3 affects DNA repair, regulates chromatin structure, and causes hepatocellular carcinoma.

Public Health Relevance

Histone deacetylase 3 (Hdac3) is a key factor controlling the expression of genes, which may be a therapeutic target for cancer therapy. This application addresses the role of this key gene in the cause, prevention, and treatment of hepatocellular carcinoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA141071-03
Application #
8217259
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Johnson, Ronald L
Project Start
2010-05-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$374,701
Indirect Cost
$134,508
Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Stengel, Kristy R; Hiebert, Scott W (2015) Class I HDACs Affect DNA Replication, Repair, and Chromatin Structure: Implications for Cancer Therapy. Antioxid Redox Signal 23:51-65
Ziesché, Elisabeth; Kettner-Buhrow, Daniela; Weber, Axel et al. (2013) The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-?B. Nucleic Acids Res 41:90-109
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
Huang, Fu; Chandrasekharan, Mahesh B; Chen, Yi-Chun et al. (2010) The JmjN domain of Jhd2 is important for its protein stability, and the plant homeodomain (PHD) finger mediates its chromatin association independent of H3K4 methylation. J Biol Chem 285:24548-61
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
Razidlo, David F; Whitney, Tiffany J; Casper, Michelle E et al. (2010) Histone deacetylase 3 depletion in osteo/chondroprogenitor cells decreases bone density and increases marrow fat. PLoS One 5:e11492