Specific and Redundant Functions of Histone Deacetylases in Regulation of Cell Cycle and Apoptosis

Zhu, Ping; Huber, E.M.; Kiefer, Franz; Göttlicher, Martin

doi:10.4161/cc.3.10.1195

Cited by 40 publications

(31 citation statements)

References 14 publications

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“…Our results show that valproate causes time-dependent increment of p21 WAF1 expression in ESS-1 cells. There are data suggesting that, at least in colonic cancer cells, HDAC2 down-regulation does not influence p21 WAF1 expression (35). Our data imply that these processes are cell and tissue specific and depend on methods and/or substances used for HDAC inhibition.…”

Section: Discussionmentioning

confidence: 75%

Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells

Hrzenjak¹,

Moinfar²,

Kremser³

et al. 2006

Molecular Cancer Therapeutics

146

108

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Covalent modifications of histone proteins, in particular deacetylation of lysine residues, are important for the regulation of gene transcription both in normal and malignant cells. These processes are controlled by histone acetyltransferases and histone deacetylases (HDAC) and have up to now not been described in solid mesenchymal tumors. The present study shows differences in the HDAC1 and HDAC2 expression in endometrial stromal sarcomas (ESS) and a cognate cell line (ESS-1) compared with nonneoplastic endometrial stroma. We show for the first time that HDAC2 expression is consistently increased in ESS. In contrast, HDAC1 expression is generally lower than HDAC2 both in nonneoplastic stroma and in ESS, suggesting that these two proteins, although closely related, are regulated in different ways. In vitro experiments with an ESS cell line showed that valproate, an inhibitor of the class I HDACs, led to significant HDAC2 decrease and to cell differentiation. HDAC2 inhibition in ESS-1 cells caused significant changes in the cell cycle by inhibiting G 1 -S transition and influencing expression of p21 WAF1 and cyclin D1. Moreover, in ESS-1 cells, increased expression of the p21 WAF1 was associated with reduction of HDAC2 expression after transfection with small interfering RNA directed against HDAC2. Our results suggest that HDAC2 might be considered as potential drug target in the therapy of ESS and that HDAC inhibitors should be further evaluated in clinical trials in ESS. [Mol Cancer Ther 2006;5(9):2203 -10]

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Section: Discussionmentioning

confidence: 75%

Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells

Hrzenjak¹,

Moinfar²,

Kremser³

et al. 2006

Molecular Cancer Therapeutics

146

108

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“…Previous studies found that HDAC2 played an important role in tumor cell proliferation, cell cycle control and other cellular processes (28,29). A high level of HDAC expression promotes tumoral cell proliferation, regulates the cell cycle, increases tumor angiogenesis, and upregulates the expression of various oncogenes (27).…”

Section: Discussionmentioning

confidence: 99%

HDAC2 regulates cell proliferation, cell cycle progression and cell apoptosis in esophageal squamous cell carcinoma EC9706 cells

Wang

et al. 2016

Oncology Letters

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Abstract.Increasing evidence has demonstrated that histone deacetylase 2 (HDAC2) participates in the regulation of a variety of biological processes in numerous tumors. However, the potential role of HDAC2 in the development and progression of esophageal squamous cell carcinoma (ESCC) remains elusive. Immunohistochemistry was utilized to detect the expression of HDAC2, Cell Counting Kit-8 was used to determine the cell proliferation, and flow cytometry was employed to investigate cell cycle and cell apoptosis. Finally, western blotting was employed to detect the protein expression of cyclin D1, p21, B cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). The present study found that expression of HDAC2 protein in ESCC tissues was significantly increased compared with atypical hyperplasia tissues and normal esophageal mucosa (P<0.001). The expression of HDAC2 was not associated with the age or gender of patients (P>0.05), but was closely associated with the histological grade, invasion depth, tumor-node-metastasis stage and lymph node metastasis, respectively (all P<0.001). HDAC2 small interfering RNA effectively downregulated the expression of HDAC2 protein in ESCC EC9706 cells. Downregulation of HDAC2 expression evidently inhibited cell proliferation, arrested cell cycle at the G0/G1 phase and induced cell apoptosis in ESCC EC9706 cells, coupled with increased expression of p21 and Bax proteins and decreased expression of cyclin D1 and Bcl-2 proteins. Overall, the present findings suggest that HDAC2 may play an important role in the development and progression of ESCC and be considered as a novel molecular target for the treatment of ESCC.

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“…The selective disruption of HDAC1 was found to result in embryonic lethality despite its elevating HDAC2 and HDAC3 expressions (26). HDAC2 seems to preferentially act to prevent apoptosis, and not act in cell cycle control similar to the specific importance of HDAC1 in cell cycle regulation (27). HDAC8 associates with the smooth muscle actin cytoskeleton and may regulate the contraction of smooth muscle cells (28).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor–Mediated Radiosensitization of Human Cancer Cells: Class Differences and the Potential Influence of p53

Kim

Shin

Kim

et al. 2006

Clinical Cancer Research

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Histone deacetylase inhibitors (HDI) are emerging as potentially useful components of the anticancer armamentarium and as useful tools to dissect mechanistic pathways. HDIs that globally inhibit histone deacetylases (HDAC) have radiosensitizing effects, but the relative contribution of specific HDAC classes remains unclear. Newly characterized HDIs are now available that preferentially inhibit specific HDAC classes, including SK7041 (inhibits class I HDACs) and splitomicin (inhibits class IIIHDACs). We investigated in human cancer cells the relative radiosensitizations that result from blocking specific HDAC classes. We found that trichostatin A (TSA; inhibitor of both class I and II HDACs) was the most effective radiosensitizer, followed by the class I inhibitor SK7041, whereas splitomicin (inhibitor of class III) had least effect. Interestingly, radiosensitization by TSA in cell lines expressing p53 was more pronounced than in isogenic lines lacking p53. Radiosensitization of cells expressing p53 by TSA was reduced by pifithrin-a, a small-molecule inhibitor of p53. In contrast, the radiosensitization by TSA of cells expressing low levels of p53 was enhanced by transfection of wild-type p53^expressing vector or pretreatment with leptomycin B, an inhibitor of nuclear export that increased intracellular levels of p53. These effects on radiosensitization were respectively muted or not seen in cells treated with SK7041or splitomicin. To our knowledge, this may be among the first systematic investigations of the comparative anticancer effects of inhibiting specific classes of HDACs, with results suggesting differences in the degrees of radiosensitization, which in some cell lines may be influenced by p53 expression.

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Specific and Redundant Functions of Histone Deacetylases in Regulation of Cell Cycle and Apoptosis

Cited by 40 publications

References 14 publications

Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells

Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells

HDAC2 regulates cell proliferation, cell cycle progression and cell apoptosis in esophageal squamous cell carcinoma EC9706 cells

Histone Deacetylase Inhibitor–Mediated Radiosensitization of Human Cancer Cells: Class Differences and the Potential Influence of p53

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