Deletion of Histone Deacetylase 3 Reveals Critical Roles in S Phase Progression and DNA Damage Control

Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Molecular cell (Impact Factor: 14.02). 05/2008; 30(1):61-72. DOI: 10.1016/j.molcel.2008.02.030
Source: PubMed

ABSTRACT Histone deacetylases (HDACs) are enzymes that modify key residues in histones to regulate chromatin architecture, and they play a vital role in cell survival, cell-cycle progression, and tumorigenesis. To understand the function of Hdac3, a critical component of the N-CoR/SMRT repression complex, a conditional allele of Hdac3 was engineered. Cre-recombinase-mediated inactivation of Hdac3 led to a delay in cell-cycle progression, cell-cycle-dependent DNA damage, and apoptosis in mouse embryonic fibroblasts (MEFs). While no overt defects in mitosis were observed in Hdac3-/- MEFs, including normal H3Ser10 phosphorylation, DNA damage was observed in Hdac3-/- interphase cells, which appears to be associated with defective DNA double-strand break repair. Moreover, we noted that Hdac3-/- MEFs were protected from DNA damage when quiescent, which may provide a mechanistic basis for the action of HDAC inhibitors on cycling tumor cells.

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Available from: Scott W Hiebert, Jun 15, 2015
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    • "The critical importance of corepressor interaction for HDAC3 activity has been recently demonstrated in vivo [172], which shows that mice harboring loss-of-function mutations in the DAD domain of both NCoR and SMRT have essentially no active HDAC3 in all tested tissues, which correlates with globally-increased histone acetylation. These mice, unlike the embryonic lethality of the total HDAC3 knockout mice [173], are vital, suggesting that free HDAC3 is not non-functional. A follow-up study by the Lazar group [174] recently showed that an HDAC3 mutant that is enzymatically inactive "
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    ABSTRACT: Nuclear receptor corepressor (NCoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) function as corepressors for diverse transcription factors including nuclear receptors such as estrogen receptors and androgen receptors. Deregulated functions of NCoR and SMRT have been observed in many types of cancers and leukemias. NCoR and SMRT directly bind to transcription factors and nucleate the formation of stable complexes that include histone deacetylase 3, transducin b-like protein 1/TBL1-related protein 1, and G-protein pathway suppressor 2. These NCoR/SMRT-interacting proteins also show deregulated functions in cancers. In this review, we summarize the literature on the mechanism, regulation, and function of the core components of NCoR/SMRT complexes in the context of their involvement in cancers and leukemias. While the current studies support the view that the corepressors are promising targets for cancer treatment, elucidation of the mechanisms of corepressors involved in individual types of cancers is likely required for effective therapy.
    10/2014; 2(3):169-187.
    • "Mechanistically, understanding of how exactly HDAC inhibitors work is not trivial as these inhibitors have global effects on gene expression rather than modulating the expression of a single cancer-relevant gene. In fact, not much is known about functions of HDACs specifically in myeloid development , as global depletion of class I HDAC genes results in early lethality [108] [109] [110], emphasizing their broad functions in the genome. However, at least some specificity can be assumed because conditional knockout studies in mice showed class I HDAC dependency for normal erythroid/megacaryocyte but not for myeloid development [110] [111]. "
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    ABSTRACT: Cellular commitment to differentiation requires a tightly synchronized, spatial-temporal interaction of regulatory proteins with the basic DNA and chromatin. A complex network of mechanisms, involving induction of lineage instructive transcription factors, installation or removal of histone modifications and changes in the DNA methylation pattern locally orchestrate the three dimensional chromatin structure and determine cell fate. Maturation of myeloid lineages from haematopoietic stem cells has emerged as a powerful model to study those principles of chromatin mechanisms in cellular differentiation and lineage fate selection. This review summarizes recent knowledge and puts forward novel ideas on how dynamics in the epigenetic landscape of myeloid cells shape the development, immune-activation and leukaemic transformation outcome.
    Journal of Molecular Biology 08/2014; 427(3). DOI:10.1016/j.jmb.2014.08.015 · 4.33 Impact Factor
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    • "Histone deacetylase inhibitors have been shown be synergistic with DNA damaging radiation (18, 61–65), suggesting a role for HDACi with DNA damaging chemotherapeutic agents. Combining HDACi with chemotherapeutic drugs that specifically target DNA, such as topoiomerase II inhibitors and cisplatin, enhance the efficacy of these drugs in cancer cells (66–68). "
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    ABSTRACT: Epithelial ovarian cancer remains the deadliest gynecologic malignancy. Despite advances in treatment, new approaches are needed. Histone deacetylases (HDACs) are a family of enzymes that regulate gene expression by removing acetyl groups from lysine residues on histones and non-histone proteins. Inhibition of HDACs with small molecules has led to the development of histone deacetylase inhibitors (HDACi) that are in clinical use, primarily for hematologic malignancies. Although clinical trials with HDACi as single agents in solid tumors have been disappointing, data from independent labs and recent work by our group show that class I selective HDACi have potent anti-tumor effects in pre-clinical models of ovarian cancer. This review summarizes the role of HDACs in ovarian cancer and the potential niche for selective class I HDACi, particularly HDAC3 in ovarian cancer therapy.
    Frontiers in Oncology 05/2014; 4:111. DOI:10.3389/fonc.2014.00111
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