Histone deacetylases: salesmen and customers in the post‐translational modification market

Brandl, André; Heinzel, Thorsten; Krämer, Oliver H.

doi:10.1042/bc20080158

Cited by 98 publications

(79 citation statements)

References 94 publications

(122 reference statements)

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“…One possibility is that HDAC2 is distinct from other HDAC members by post-translational modifications. It has been shown that HDAC2 protein is regulated by lysine ubiquitination, serine phosphorylation, tyrosine nitration, and cysteine nitrosylation (Sun et al 2002;Kramer et al 2003;Nott et al 2008;Adenuga et al 2009;Brandl et al 2009;Osoata et al 2009). Other ubiquitin conjugation and ligation enzymes have also been implicated in HDAC2 destruction.…”

Section: Discussionmentioning

confidence: 99%

Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2

Zhang¹,

Kan²,

Huang³

et al. 2011

Genes Dev.

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Histone deacetylases (HDACs) are major epigenetic modulators involved in a broad spectrum of human diseases including cancers. Administration of HDAC inhibitors (HDACis) leads to growth inhibition, differentiation, and apoptosis of cancer cells. Understanding the regulatory mechanism of HDACs is imperative to harness the therapeutic potentials of HDACis. Here we show that HDACi-and DNA damage-induced apoptosis are severely compromised in mouse embryonic fibroblasts lacking a HECT domain ubiquitin ligase, Mule (Mcl-1 ubiquitin ligase E3). Mule specifically targets HDAC2 for ubiquitination and degradation. Accumulation of HDAC2 in Mule-deficient cells leads to compromised p53 acetylation as well as crippled p53 transcriptional activation, accumulation, and apoptotic response upon DNA damage and Nutlin-3 treatments. These defects in Mule-null cells can be partially reversed by HDACis and fully rescued by lowering the elevated HDAC2 in Mule-null cells to the normal levels as in wild-type cells. Taken together, our results reveal a critical regulatory mechanism of HDAC2 by Mule and suggest this pathway determines the cellular response to HDACis and DNA damage.

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Section: Discussionmentioning

confidence: 99%

Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2

Zhang¹,

Kan²,

Huang³

et al. 2011

Genes Dev.

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“…HDACs play a crucial role in removing the acetyl groups from histones, thus providing a regulatory role toward the epigenetic control of gene expression (17). Presence of HDACs within the gene regulatory regions leads to formation of closed chromatin complexes (heterochromatin) resulting in gene silencing.…”

Section: Histone Deacetylasesmentioning

confidence: 99%

Oxidative Stress and Chromatin Remodeling in Chronic Obstructive Pulmonary Disease and Smoking-Related Diseases

Sundar

Yao

Rahman

2013

Antioxidants & Redox Signaling

162

107

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Significance: Chronic obstructive pulmonary disease (COPD) is predominantly a tobacco smoke-triggered disease with features of chronic low-grade systemic inflammation and aging (inflammaging) of the lung associated with steroid resistance induced by cigarette smoke (CS)-mediated oxidative stress. Oxidative stress induces various kinase signaling pathways leading to chromatin modifications (histone acetylation/deacetylation and histone methylation/demethylation) in inflammation, senescence, and steroid resistance. Recent Advances: Histone mono-, di-, or tri-methylation at lysine residues result in either gene activation (H3K4, H3K36, and H3K79) or repression (H3K9, H3K27, and H3K20). Cross-talk occurs between various epigenetic marks on histones and DNA methylation. Both CS and oxidants alter histone acetylation/deacetylation and methylation/ demethylation leading to enhanced proinflammatory gene expression. Chromatin modifications occur in lungs of patients with COPD. Histone deacetylase 2 (HDAC2) reduction (levels and activity) is associated with steroid resistance in response to oxidative stress. Critical Issues: Histone modifications are associated with DNA damage/repair and epigenomic instability as well as premature lung aging, which have implications in the pathogenesis of COPD. HDAC2/SIRTUIN1 (SIRT1)-dependent chromatin modifications are associated with DNA damage-induced inflammation and senescence in response to CS-mediated oxidative stress. Future Directions: Understanding CS/oxidative stress-mediated chromatin modifications and the cross-talk between histone acetylation and methylation will demonstrate the involvement of epigenetic regulation of chromatin remodeling in inflammaging. This will lead to identification of novel epigenetic-based therapies against COPD and other smoking-related lung diseases. Pharmacological activation of HDAC2/SIRT1 or reversal of their oxidative post-translational modifications may offer therapies for treatment of COPD and CS-related diseases based on epigenetic histone modifications.

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“…Deacetylases are frequently dysregulated in numerous tumors (7,8), Histone deacetylase 2 (HDAC2), an important member of type I histone deacetylases, plays a crucial role in tumor onset and development (8,9). Increasing evidence has revealed that HDAC2 is often overexpressed in various types of tumors (10)(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

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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Histone deacetylases: salesmen and customers in the post‐translational modification market

Cited by 98 publications

References 94 publications

Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2

Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2

Oxidative Stress and Chromatin Remodeling in Chronic Obstructive Pulmonary Disease and Smoking-Related Diseases

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

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