Metformin Increased Histone Deacetylases 1, 3, and 8 Expressions as Epigenetic Regulators in Type 2 Diabetic Patients.

Strategies to induce fetal hemoglobin (HbF) synthesis for the treatment of β-hemoglobinopathies probably involve protein modifications by histone deacetylases (HDACs) that mediate γ-globin gene regulation. However, the role of individual HDACs in globin gene expression is not very well understood; thus, the focus of our study was to identify HDACs involved in γ-globin activation. K562 erythroleukemia cells treated with the HbF inducers hemin, trichostatin A, and sodium butyrate had significantly reduced mRNA levels of HDAC9 and its splice variant histone deacetylase-related protein. Subsequently, HDAC9 gene knockdown produced dose-dependent γ-globin gene silencing over an 80-320 nm range. Enforced expression with the pTarget-HDAC9 vector produced a dose-dependent 2.5-fold increase in γ-globin mRNA (p < 0.05). Furthermore, ChIP assays showed HDAC9 binding in vivo in the upstream Gγ-globin gene promoter region. To determine the physiological relevance of these findings, human primary erythroid progenitors were treated with HDAC9 siRNA; we observed 40 and 60% γ-globin gene silencing in day 11 (early) and day 28 (late) progenitors. Moreover, enforced HDAC9 expression increased γ-globin mRNA levels by 2.5-fold with a simultaneous 7-fold increase in HbF. Collectively, these data support a positive role for HDAC9 in γ-globin gene regulation.

Treatment with histone deacetylase (HDAC) inhibitors, such as valproic acid, increases survival in animal models of trauma and sepsis. Valproic acid is a pan-inhibitor that blocks most of the known HDAC isoforms. Targeting individual HDAC isoforms may increase survival and reduce complications, but little is known of the natural history of HDAC gene expression following trauma. We hypothesized that distinct HDAC isoform gene expression patterns would be associated with differences in outcomes following trauma. Twenty-eight-day longitudinal HDAC leukocyte gene expression profiles in 172 blunt trauma patients were extracted from the Inflammation and the Host Response to Injury (Glue Grant) data set. Outcome was classified as complicated (death or no recovery by Day 28, n = 51) or uncomplicated (n = 121). Mixed modeling was used to compare the HDAC expression trajectories between the groups, corrected for Injury Severity Score (ISS), base deficit, and volume of blood products transfused during the initial 12 hours following admission. Weighted gene correlation network analysis identified modules of genes with significant coexpression, and HDAC genes were mapped to these modules. Biologic function of these modules was investigated using the Gene Ontology database. Elevated longitudinal HDAC expression trajectories for HDAC1, HDAC3, HDAC6, and HDAC11 were associated with complicated outcomes. In contrast, suppressed expression of Sirtuin 3 (SIRT3) was associated with adverse outcome (p < 0.01). Weighted gene correlation network analysis identified significant coexpression of HDAC and SIRT genes with genes involved in ribosomal function and down-regulation of protein translation in response to stress (HDAC1), T-cell signaling, and T-cell selection (HDAC3) as well as coagulation and hemostasis (SIRT3). No coexpression of HDAC11 was identified. Expression trajectories of HDAC1, HDAC3, HDAC6, HDAC11, and SIRT3 correlate with outcomes following trauma and may potentially serve as biomarkers. They may also be promising targets for pharmacologic intervention. The effects of HDAC and SIRT gene expression in trauma may be mediated through pathways involved in ribosomal and T-cell function as well as coagulation and hemostasis. Prognostic study, level III.

Abstract #2051 Background: Excess histone deacetylase (HDAC) activity can induce global hypoacetylation of histone and non-histone protein substrates, altering gene expression patterns and cell behavior potentially associated with malignant transformation. However, HDAC expression and protein acetylation have not previously been studied in the context of breast cancer progression.&amp;#x2028; Materials and Methods: We performed immunohistochemistry (IHC) to assess expression levels of acetylated histone H4 (acH4), acH4K12, acTubulin, HDAC1, HDAC2 and HDAC6 in formalin fixed paraffin embedded sections with synchronous normal epithelium (N), ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) components from 58 archived samples at UCSF. Staining was assessed on the basis of H-score, defined as the sum of the intensity of staining (0-3) multiplied by % of stained cells for each intensity (score range 0-300). H-score differences between groups were tested for significance using either the Mann-Whitney test or the Wilcoxon signed rank test for paired samples.&amp;#x2028; Results: From N to DCIS, there was a marked reduction in histone acetylation (acH4, acH4K12). Tubulin acetylation, a marker of non-histone protein acetylation, showed a smaller reduction. Expression of all three HDACs was also reduced, but to a lesser extent than histone acetylation. Moreover, from DCIS to IDC, the same pattern of changes in acetylation and HDAC expression was seen, although these differences were of smaller magnitude than between N and DCIS. All markers were significantly different between N and DCIS (all p&amp;lt;0.0001) and between DCIS and IDC (all p&amp;lt;0.03). ER-negative tumors exhibited greater changes from N to DCIS than did ER-positive tumors, particularly for acH4 and HDAC1 (p=0.05 and 0.0001 respectively). High-grade invasive tumors showed more significant changes from N to DCIS than low/intermediate grade tumors for acH4, acH4K12, acTubulin, and HDAC1 (p=0.0009, 0.006, 0.05, and &amp;lt;0.0001 respectively). The change in protein acetylation and HDAC expression with cancer progression did not differ by HER2 status or age (≤50 or &amp;gt;50).&amp;#x2028; &amp;#x2028; Conclusions: Overall there was a pattern of hypoacetylation associated with malignant progression, with normal epithelium exhibiting the highest acH4, acH4K12, and acTubulin levels and IDC exhibiting the lowest levels. Paradoxically, expression of HDAC 1, 2 and 6 was not increased; thus, our data support that histone hypoacetylation is not regulated by HDAC expression but rather by modulation of HDAC activity. Outcome studies and clinical trials are needed to assess the prognostic significance of these findings and to determine how effectively HDAC inhibitors could reverse the hypoacetylation observed in progression from N to DCIS and IDC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2051.

The expression levels of histone deacetylase 2 (HDAC2), eukaryotic initiation factor 5 (eIF5), and eukaryotic initiation factor 6 (eIF6), and relationship between HDAC2 and eIF5 or eIF6 in lung cancer tissues were investigated, in order to charify the relationship between HDAC2 and the prognosis of lung cancer patients and its influence on the expression of eIF5 and eIF6. The expression of HDAC2, eIF5, and eIF6 in lung cancer tissues was detected by quantitative reverse transcription polymerase chain reaction. The expression correlation between HDAC2 and eIF5 or eIF6 was tested using a t test. The correlation between HDAC2 and eIF5 or eIF6 was analyzed using the TCGA database. The identified cells were constructed with small interfering siRNA and HDAC2 overexpression plasmid. The proliferation and migration ability of the identified cells was investigated by CCK8 and Transwell assays, respectively. HDAC2, eIF5, and eIF6 were overexpressed in lung cancer tissues, and HDAC2 expression level was negatively correlated with the prognosis of lung cancer patients. HDAC2 expression level was positively correlated with eIF5 and eIF6 expression levels. HDAC2 could regulate the expression of eIF5 and eIF6. The regulation of proliferation and invasion of lung cancer cells by HDAC2 depended on eIF5 and eIF6. HDAC2, eIF5, and eIF6 were closely related with lung cancer tumorigenesis, which might be potential biological markers and therapeutic targets for lung cancer.

Background: A variety of studies have reported the associations between histone deacetylases (HDACs) genes and cardio-cerebrovascular diseases. The identification of variants in the HDACs genes and the determination of risk alleles could open novel therapeutic avenues for these diseases. This article summarized variants in HDACs genes and different sub-types of cardio-cerebrovascular diseases. Methods: A comprehensive literature search was conducted across PubMed, Web of Science and Scopus databases to identify studies published prior to 27 June 2025. We registered this protocol in the PROSPERO database (CRD420251010100). The Venice Criteria were applied to assess the statistically significant associations identified by meta-analyses. The single-nucleotide polymorphisms were mapped to their corresponding genes, and functional annotation was conducted using the Encyclopedia of DNA Elements tool, HaploReg and the UCSC Genome browser. Results: We finally included 34 published studies and 160 datasets to assess the associations between variants in HDAC genes and cardio-cerebrovascular diseases. Rs2107595 in HDAC 9 was the variant found to be associated with four sub-types identified by genome-wide association study or meta-analyses. Rs11984041 was related to ischemic stroke. Rs10230207 and rs2192476 were associated with intracranial aneurysm. Conclusions: HDACs genes were associated with multiple cardio-cerebrovascular diseases. However, ethnic disparities were observed in their effects. Therefore, ethnicity-targeted treatments, including specific HDAC inhibitors, should be developed in the future.

The immunohistochemical expression and potential prognostic value of HDAC6 and AR in invasive breast cancer

Histone deacetylases (HDACs) and sirtuins (SIRTs) are important epigenetic regulators of cancer pathways. There is a limited understanding of how transcriptional regulation of their genes is affected by chemotherapeutic agents, and how such transcriptional changes affect tumour sensitivity to drug treatment. We investigated the concerted transcriptional response of HDAC and SIRT genes to 15 approved antitumor agents in the NCI-60 cancer cell line panel. Antitumor agents with diverse mechanisms of action induced upregulation or downregulation of multiple HDAC and SIRT genes. HDAC5 was upregulated by dasatinib and erlotinib in the majority of the cell lines. Tumour cell line sensitivity to kinase inhibitors was associated with upregulation of HDAC5, HDAC1, and several SIRT genes. We confirmed changes in HDAC and SIRT expression in independent datasets. We also experimentally validated the upregulation of HDAC5 mRNA and protein expression by dasatinib in the highly sensitive IGROV1 cell line. HDAC5 was not upregulated in the UACC-257 cell line resistant to dasatinib. The effects of cancer drug treatment on expression of HDAC and SIRT genes may influence chemosensitivity and may need to be considered during chemotherapy.

Simple SummaryEpigenetic processes contribute to the regulation of the immune system by activating multiple transcriptional changes, which in turn, are the product of immune cell reprogramming. Given that the deregulation of these mechanisms promotes cancer progression by altering the balance of genes controlling cell proliferation and death, the objective of this study was to identify a genetic/epigenetic/immunological colorectal cancer signature through a preliminary in silico analysis aimed at identifying the pathogenic causes of colorectal cancer associated with expression levels of histone deacetylase 2 (HDAC2) and two immune system regulators, class II major histocompatibility complex transactivator (CIITA) and beta-2 microglobulin (B2M), in a cohort of patients harboring a common dysregulation of these genes. We next extended the study by investigating a tissue microarray cohort of colorectal cancer patients from a diagnostic/prognostic perspective.A large body of clinical and experimental evidence indicates that colorectal cancer is one of the most common multifactorial diseases. Although some useful prognostic biomarkers for clinical therapy have already been identified, it is still difficult to characterize a therapeutic signature that is able to define the most appropriate treatment. Gene expression levels of the epigenetic regulator histone deacetylase 2 (HDAC2) are deregulated in colorectal cancer, and this deregulation is tightly associated with immune dysfunction. By interrogating bioinformatic databases, we identified patients who presented simultaneous alterations in HDAC2, class II major histocompatibility complex transactivator (CIITA), and beta-2 microglobulin (B2M) genes based on mutation levels, structural variants, and RNA expression levels. We found that B2M plays an important role in these alterations and that mutations in this gene are potentially oncogenic. The dysregulated mRNA expression levels of HDAC2 were reported in about 5% of the profiled patients, while other specific alterations were described for CIITA. By analyzing immune infiltrates, we then identified correlations among these three genes in colorectal cancer patients and differential infiltration levels of genetic variants, suggesting that HDAC2 may have an indirect immune-related role in specific subgroups of immune infiltrates. Using this approach to carry out extensive immunological signature studies could provide further clinical information that is relevant to more resistant forms of colorectal cancer.

Roses have high economic values as garden plants and for cut-flower and cosmetics industries. The growth and development of rose plants is affected by exposure to high temperature. Histone acetylation plays an important role in plant development and responses to various stresses. It is a dynamic and reversible process mediated by histone deacetylases (HDAC) and histone acetyltransferases (HAT). However, information on HDAC and HAT genes of roses is scarce. Here, 23 HDAC genes and 10 HAT genes were identified in the Rosa chinensis ‘Old Blush’ genome. Their gene structures, conserved motifs, physicochemical properties, phylogeny, and synteny were assessed. Analyses of the expression of HDAC and HAT genes using available RNAseq data showed that these genes exhibit different expression patterns in different organs of the three analyzed rose cultivars. After heat stress, while the expression of most HDAC genes tend to be down-regulated, that of HAT genes was up-regulated when rose plants were grown at high-temperature conditions. These data suggest that rose likely respond to high-temperature exposure via modification in histone acetylation, and, thus, paves the way to more studies in order to elucidate in roses the molecular mechanisms underlying rose plants development and flowering.

Background: The prognostic significance and biological functions of the histone deacetylases (HDACs) gene family in liver hepatocellular carcinoma (LIHC) have not been fully investigated. Methods: Using Kaplan-Meier and Cox regression analysis, this study determined if HDAC genes were relevant for prognosis in LIHC. A regression model utilizing HDAC genes and the least absolute shrinkage and selection operator (LASSO) was created to foretell LIHC risk. A selective inhibitor of endogenous HDACs, CKD-581, was studied in vitro and in vivo to determine its effects on the development, invasion, migration, and proliferation of LIHC cell lines. Results: Six HDACs were identified as correlating with the prognosis of LIHC. Overall survival (OS) was found to be shorter in individuals with higher risk scores when compared to those with lower risk scores, according to survival study. Natural killer cell infiltration was higher in individuals with lower risk ratings, which was mainly explained by the type II interferon (IFN) response. Limiting the activity of endogenous HDACs caused LIHC cell death by preventing their migration, invasion, and proliferation. In vivo studies confirmed that blocking HDAC expression inhibited tumor growth in mice. Further mechanistic studies showed that inhibition of HDACs expression elevates the protein levels of P21 and P27, and reduces those of cyclins A2, B1, D1 and E1. Conclusions: The risk score prognostic model based on HDAC genes could provide a valuable prognostic biomarker for LIHC. CKD-581 prohibits LIHC progression via inhibiting the cell cycle signaling pathway. CKD-581 holds promise as a therapeutic agent for the clinical management of LIHC.

Background: Chromatin is dynamic in higher-order structure in response to extracellular and environmental signals. We observed nuclear morphological changes in clinical cancer tissues after chemotherapy. Since chromatin structure dictates gene expression, and therefore function, further investigation of this phenomenon may help us to better understand therapeutic responses. We hypothesise that nuclear morphological changes in cancer in response to DNA-damage by chemotherapy are mediated by histone deacetylases (HDACs). Methods: Ovarian cancer cell lines PEO1/PEO4 (platinum sensitive/resistant) were selected as in vitro models, and primary ovarian cancer xenografts OV1002 and HOX424 as in vivo models. Expression levels of HDACs and heterochromatin protein 1 (HP1) were screened by reverse phase protein array (RPPA) and western blot after treatment with cisplatin. Immunofluorescence imaging was undertaken using confocal microscopy and nuclear texture was measured in Image J using GLCM texture analysis plugin. 38 ovarian cancer patient and 175 xenograft samples were assessed for HDAC and HP1 expression in response to chemotherapy by quantitative immunofluorescence. HDAC2 expression was modulated by interfering RNAs (siRNA). Results: We demonstrate nuclear morphological changes in clinical tumours, xenografts, and cell lines in response to platinum chemotherapy. HDACs and HP1 isoforms showed differential expression in a panel of 25 ovarian cancer cell lines associated with response to chemotherapy with increased expression in treated or resistant lines. Expression of HDACs increased in PEO1 cells treated with cisplatin in a time-dependent fashion. This was accompanied by quantifiable changes in nuclear texture (increased heterogeneity), and high expression of HP1s at early time point (4-24h). The proliferation of PEO1 cells was inhibited and HP1 protein expression decreased after HDAC2 knockdown. In clinical specimens, HDAC8 and HP1 gamma expression significantly increased after chemotherapy, and class I HDAC (1, 2, and 8) and HP1 expression were increased after carboplatin treatment in carboplatin-sensitive xenografts. Chromatin conformation, DNA damage response, and cell cycle progression showed sequential changes over time with carboplatin treatment. Conclusion: These results demonstrate alterations in chromatin structure after chemotherapy, and implicate the role of class I HDACs in higher order chromatin changes and the DNA damage response in ovarian cancer in vitro and in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4085. doi:1538-7445.AM2012-4085

A Centrosomal Cdc20-APC Pathway Controls Dendrite Morphogenesis in Postmitotic Neurons

Increased Gene Expression of Histone Deacetylases In Patients with Philadelphia-Negative Chronic Myeloproliferative Neoplasms

Survivin is an oncogenic protein that is highly expressed in breast cancer and has a dual function that is dependent on its subcellular localization. In the cytosol, survivin blocks programmed cell death by inactivating caspase proteins; however, in the nucleus it facilitates cell division by regulating chromosomal movement and cytokinesis. In prior work, we showed that survivin is acetylated by CREB-binding protein (CBP), which restricts its localization to the nuclear compartment and thereby inhibits its anti-apoptotic function. Here, we identify histone deacetylase 6 (HDAC6) as responsible for abrogating CBP-mediated survivin acetylation in the estrogen receptor (ER)-positive breast cancer cell line, MCF-7. HDAC6 directly binds survivin, an interaction that is enhanced by CBP. In quiescent breast cancer cells in culture and in malignant tissue sections from ER+ breast tumors, HDAC6 localizes to a perinuclear region of the cell, undergoing transport to the nucleus following CBP activation where it then deacetylates survivin. Genetically modified mouse embryonic fibroblasts that lack mhdac6 localize survivin predominantly to the nuclear compartment, whereas wild-type mouse embryonic fibroblasts localize survivin to distinct cytoplasmic structures. Together, these data imply that HDAC6 deacetylates survivin to regulate its nuclear export, a feature that may provide a novel target for patients with ER+ breast cancer.

The prefrontal cortex (PFC), a region responsible for high-order cognitive functions, such as decision-making, attention and working memory, is highly influenced by stress and corticosteroid stress hormones. Recently it has been shown that acute stress affects PFC functions by potentiating glutamatergic transmission via a mechanism dependent on glucocorticoid receptor (GR) and its downstream target, serum and glucocorticoid-inducible kinase (SGK). To identify the key regulators of stress responses, we examined the role of histone deacetylase 6 (HDAC6), a unique member of the HDAC family that could regulate the GR chaperone protein heat shock protein 90 (HSP90), in the synaptic action of acute stress in PFC. We found that HDAC6 inhibition or knockdown blocked the enhancement of glutamatergic transmission and glutamate receptor trafficking by acute stress in vivo or corticosterone treatment in vitro. In addition, HDAC6 inhibition blocked the up-regulation of SGK in animals exposed to acute stress. HSP90 inhibition or knockdown produced a similar blockade of the acute stress-induced enhancement of glutamatergic signalling. These findings have identified HDAC6 as a key molecule gating the effects of acute stress on synaptic functions in the PFC.