• Journal of Plant Biotechnology
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• v.50
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• pp.232-238
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• 2023

Histone deacetylases (HDACs) play a pivotal role in epigenetic regulation, affecting the structure of chromatin and gene expression across different stages of plant development and in response to environmental stresses. Although the role of HDACs in Arabidopsis and rice has been focused on in extensive research, the role of the HDAC gene family in various medicinal plants remains unclear. In the genome of the balloon flower (Platycodon grandiflorus), we identified 10 putative P. grandiflorus HDAC (PlgHDAC) proteins, which were classified into the three families (RPD3/HDA1, SIR2, and HD2 HDAC families) based on their domain compositions. These HDACs were predicted to be localized in various cellular compartments, indicating that they have diverse functions. In addition, the tissue-specific expression profiles of PlgHDACs differed across different plant tissues, indicating that they are involved in various developmental processes. Furthermore, the expression levels of all PlgHDACs were upregulated in leaves after waterlogging treatment, implying their potential role in coping with waterlogging-induced stress. Overall, our findings provide a comprehensive foundation for further research into the epigenetic regulation of PlgHDACs, and particularly, on their functions in response to environmental stresses such as waterlogging. Understanding the roles of these HDACs in the development and stress responses of balloon flower could have significant implications for improving crop yield and the quality of this important medicinal plant.

• Journal of Integrative Natural Science
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• v.6 no.1
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• pp.57-63
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• 2013

Histone deacetylase (HDACs) is an enzyme family that deacetylates histones and non-histones protein. Availability of crystal structure of HDAC8 has been a boosting factor to generate target based inhibitors. Hydroxamic class is the most studied one to generate potent inhibitors. HDAC class I and class II enzymes are emerging as a therapeutic target for cancer, diabetes, inflammation and other diseases. DNA methylation and histone modification are epigenetic mechanism, is important for the regulation of cellular functions. HDACs enzymes play essential role in gene transcription to regulate cell proliferation, migration and death. The aim of this article is to provide a comprehensive overview about structure and function of HDACs enzymes, histone deacetylase inhibitors (HDACi) and HDACs enzymes as a therapeutic target for cancer, inflammation and diabetes.

• BMB Reports
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• v.48 no.3
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• pp.131-138
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• 2015

Cardiac hypertrophy is a form of global remodeling, although the initial step seems to be an adaptation to increased hemodynamic demands. The characteristics of cardiac hypertrophy include the functional reactivation of the arrested fetal gene program, where histone deacetylases (HDACs) are closely linked in the development of the process. To date, mammalian HDACs are divided into four classes: I, II, III, and IV. By structural similarities, class II HDACs are then subdivided into IIa and IIb. Among class I and II HDACs, HDAC2, 4, 5, and 9 have been reported to be involved in hypertrophic responses; HDAC4, 5, and 9 are negative regulators, whereas HDAC2 is a pro-hypertrophic mediator. The molecular function and regulation of class IIa HDACs depend largely on the phosphorylation-mediated cytosolic redistribution, whereas those of HDAC2 take place primarily in the nucleus. In response to stresses, posttranslational modification (PTM) processes, dynamic modifications after the translation of proteins, are involved in the regulation of the activities of those hypertrophy-related HDACs. In this article, we briefly review 1) the activation of HDAC2 in the development of cardiac hypertrophy and 2) the PTM of HDAC2 and its implications in the regulation of HDAC2 activity.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.3
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• pp.1403-1410
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• 2014

Epigenetic regulators like histone deacetylases (1 and 2), and viral onco-proteins (E6/E7) are known to be overexpressed in cervical cancer cells. The present study was designed to investigate the effect of curcumin on HDACs (1 and 2) and HPV E6/E7 in the cervical cancer cell line SiHa and a drug resistant clone $SiHa^R$ (derived from SiHa). It was further intended to investigate whether curcumin could sensitize the cells towards cisplatin induced cell killing by modulation of multi drug resistant proteins like MRP1 and Pgp1. Curcumin inhibited HDACs, HPV expression and differentially increased acetylation and up-regulation of p53 in SiHa and $SiHa^R$, leading to cell cycle arrest at G1-S phase. Up-regulation of pRb, p21, p27 and corresponding inhibition of cyclin D1 and CDK4 were observed. Cisplatin resistance in $SiHa^R$ due to over-expression of MRP1 and Pgp1 was overcome by curcumin. Curcumin also sensitized both the cervical cancer cells towards cisplatin induced cell killing. Inhibition of HDACs and HPVs led to cell cycle arrest at G1/S phase by alteration of cell cycle regulatory proteins. Suppression of MRP1 and Pgp1 by curcumin resulted in sensitization of cervical cancer cells, lowering the chemotherapeutic dose of the drug cisplatin.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.4
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• pp.2503-2508
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• 2013

Histone deacetylation mediated by histone deacetylases (HDACs) has been reported as one of the epigenetic mechanisms associated with tumorigenesis. The poor responsiveness of anticancer drugs found with cholangiocarcinoma (CCA) leads to short survival rate. We aimed to investigate mRNA expression of HDACs class I and II, and the effect of HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA), in CCA in vitro. Expression of HDACs was studied in CCA cell lines (M213, M214 and KKU-100) and an immortal cholangiocyte (MMNK1) by semi-quantitative reverse transcription-PCR. SAHA and VPA, as well as a classical chemotherapeutic drug 5 -fluorouacil (5-FU) were used in this study. Cell proliferation was determined by sulforhodamine assay. $IC_{50}$ and $IC_{20}$ were then analyzed for each agent and cell line. Moreover, synergistic potentional of VPA or SAHA in combination with 5-FU at sub toxic does ($IC_{20}$) of each agent was also evaluated. Statistic difference of HDACs expression or cell proliferation in each experimental condition was analyzed by Student's t-test. The result demonstrated that HDACs were expressed in all studied cell types. Both SAHA and VPA inhibited cell proliferation in a dose-dependent manner. Interestingly, KKU-100 which was less senstitive to classical chemotheraoeutic 5-FU was highly was sensitive to HDAC inhibitors. Simultaneous combination of subtoxic doses of HDAC inhibitors and 5-FU signiicantly inhibited cell proliferation in CCA cell lines compared to single sgent treatment($P{\leq}0.01$), while sequentially combined treatments were less effective. The present study showed inhibitory effects of HDACIs on cell proliferation in CCA cell lines, with synergistic antitumor potential demonstrated by simultaneous combination of VPA or SAHA with 5-FU, suggesting a novel alternative therapeutic strategy in effective treatment of CCA.

• Bulletin of the Korean Chemical Society
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• v.34 no.5
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• pp.1487-1493
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• 2013

Based on the finding that the 2-aminobenzamido group of MS-275 plays a crucial role in inhibiting HDACs through chelation of zinc existing at the active site of HDAC enzymes, novel N-(2-hydroxyphenyl)arylsulfonamide derivatives were synthesized for their potential ability to inhibit HDACs and evaluated for anticancer activity against human breast cancer cell line (MCF-7). Although the synthesized arylsulfonamides have failed to significantly inhibit total HDACs activity, phenyl carbamate-linked arylsulfonamide 10 and benzyl thiocarbamate-linked arylsulfonamide 15 exhibited good anticancer activities, which were only 4.3- and 3.6-fold lower anticancer activities, respectively, than MS-275 that is undergoing phase II clinical trials. These results suggest that these compounds may act as a selective HDAC inhibitor and probably N-(2-hydroxyphenyl) sulfamoyl group may play an important role in interacting with HDAC enzymes through chelation of zinc ion.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.7
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• pp.3605-3610
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• 2016

Background: Histone acetylation in chromatin structures plays a key role in regulation of gene transcription and is strictly controlled by histone acetyltransferase (HAT) and deacetylase (HDAC) activities. HDAC deregulation has been reported in several cancers. Materials and Methods: The expression of 10 HDACs (including HDAC class I and II) was studied by quantitative reverse transcription-PCR (qRT-PCR) in a cohort of mesenchymal stem cells (MM-MSCs) from 10 multiple myeloma patients with a median age 60y. The results were compared with those obtained for normal donors. Then, a coculture system was performed between MM-MSCs and u266 cell line, in the presence or absence of sodium butyrate (NaBT), to understand the effects of HDAC inhibitors (HDACi) in MM-MSCs on multiple myeloma cases. Also, the interleukin-6 (IL-6) and vascular endothelial growth factor (VEGFA) gene expression level and apoptotic effects were investigated in MM-MSCs patients and control group following NaBT treatment. Results: The results indicated that upregulated (HDACs) and downregulated (IL6 and VEGFA) genes were differentially expressed in the MM-MSCs derived from patients with multiple myeloma and ND-MSCs from normal donors. Comparison of the MM-MSCs and ND-MSCs also showed distinct HDACs expression patterns. For the first time to our knowledge, a significant increase of apoptosis was observed in coculture with MM-MSCs treated with NaBT. Conclusions: The obtained findings elucidate a complex set of actions in MSCs in response to HDAC inhibitors, which may be responsible for anticancer effects. Also, the data support the idea that MSCs are new therapeutic targets as a potential effective strategy for MM.

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.6 no.2
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• pp.165-170
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• 2020

Histone Deacetylases (HDACs) are enzymes that have control gene expression regulation and cell state. In additions, inhibitions of HDACs are associated with growth arrest, differentiation, or apoptosis of tumor cell. Thus HDAC inhibition is one of the interesting biological targets. A variety of HDAC inhibitors has been developed by many scientists, and some of chemical structures related with HDAC inhibitors were modified to give radiolabeled HDAC inhibitors for positron emission tomography (PET) study. In this highlight review, the development of radiolabeled HDAC inhibitors for PET study are described.

• Molecular & Cellular Toxicology
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• v.2 no.3
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• pp.166-169
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• 2006

Accumulated evidences have established that aberrant regulation of histone deacetylases (HDACs) is one of major causes for development of human malignancies. Mammalian HDACs can be divided into three subclasses consisting of 11 homologous of HDACs and 7 of sirtuins, but little is known about HDAC2 causes for carcinogenesis in solid tumors. Here, in order to investigate the roles of HDAC2 in carcinogenesis of liver cancer progression, we analyzed the expression of HDAC2 in 62 human hepatocellular carcinomas by utilizing Immunohistochemistry. Moderate to strong expression of HDAC2 was found in 54 (87%) out of total 62 tumors. The majority of positive tumors were detected in nucleous, but normal hepatocytes did not express of HDAC2 or showed weak positive staining. Interestingly, we were also noted that HDAC2 expression was appeared to be associated with aggressiveness of the tumors by the fact that HDAC2 expression was observed with significances in high grade tumors (Edmonson grade II, III). Taken together, we found the aberrant expression of HDAC2 in hepatocellular carcinomas, and this suggests that HDAC2 may play an important role in the development of liver cancer.

• Radiation Oncology Journal
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• v.23 no.2
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• pp.116-122
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• 2005

Purpose: Histone deacetylase inhibitors (HDIs) are emerging as potentially useful components of anticancer therapy and their radiosensitizing effects have become evident. Specific HDAS are now available that preferentially inhibit specific HDAC classes; TSA inhibits Class I and II HDACs, and SK7041 inhibits Class I HDACs. Materials and methods: We tested the differential radiosensitization induced by two different classes of HDIs in HeLa cells. We next tested the hypothesis that p53 expression in cancer cells may influence the susceptibility to HDIs by using pharmacologic modification of the p53 status under an isogenic background. Results: It is interesting that p53 expression in the HeLa cells clearly increased the degree of radio-sensitization by TSA compared to that of the class I specific inhibitor SK7041. This suggests that p53 may, in part, be responsible for the mechanistic role for the greater radiosensitization induced by Class I & II inhibitors compared to that of the class I specific inhibitors. Thus, these studies are useful in distinguishing between events mediated solely by the Class I HDACS versus those events involving the other classes of HDACS as well. Conclusion: The anticancer efficacy of targeting Class I and II HDACS, in conjunction with radiation therapy, may be further enhanced by the restoration of p53 expression.