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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Several studies have demonstrated that protein–protein interactions control the expression of HDACs through: (a) alternative RNA splicing; (b) the modulation of the availability of cofactors; (c) varied subcellular localization; and (d) different degrees of proteolytic processing (Gallinari et al., 2007; Seto and Yoshida, 2014). Individual HDAC proteins, especially HDAC1 and HDAC2, are generally low in enzyme activity; however, when associated with protein complexes such as Sin3, nucleosome remodeling and deacetylase (NuRD), and co-repressor for element-1-silencing transcription factor (CoREST), they exhibit enhanced function, indicating the importance of protein–protein interactions in controlling their biological activity (Banks et al., 2018).
Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
Histone deacetylases (HDAC) are a superfamily of zinc-dependent enzymes that have varying biological roles; they are subclassified into four groups, i.e. I, Ha, IIb, and IV [102]. HDAC inhibitors have been used successfully in vitro and in vivo in the treatment of a wide variety of malignancies. In fact, Vorinostat was the first HDAC inhibitor to receive FDA approval for the treatment of cutaneous T-cell lymphoma [103]. It has since been shown to improve median overall survival in recurrent glioblastoma multiforme and advanced non-small cell lung cancer [104, 105]. However, this drug is a non-specific HDAC inhibitor of all classes of HDACs. Given the varying important biological functions of HDACs, global inhibition can be associated with important side effects. Thus, an impetus exists for selective targeting of HDACs. Chromatin immunoprecipitation assays have confirmed an MYC binding motif in the HDAC2 promoter region; hence, MYC-amplified tumors would serve as good targets for selective HDAC2 inhibitors [106]. In fact, depletion of HDAC2 in medulloblastoma has been shown to be cytotoxic [106]. The class Ila HDACs, HDAC5 and 9, have been shown to be upregulated in patients with aggressive high-risk medulloblastoma [107]. In turn, silencing HDAC5 and 9 expressions via siRNA led to a reduction in medulloblastoma tumor cell growth in vitro [107].
Epigenetic Modifications of Histones
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
George Rasti, Alejandro Vaquero
Oocytes remain arrested during prophase of the first meiotic division (prophase-I) for decades in humans. This prophase-I arrest is highly conserved in metazoans and is critical for oocyte differentiation because allows the oocyte to accumulate maternal components to ensure completion of oogenesis and activation of the embryonic genome upon fertilization. The oocyte contains histone-bound maternal DNA acquired during oogenesis comprising PTMs related to stalled metaphase-II. The most important difference between the chromatin of oocytes and of somatic nuclei is the absence of somatic linker histone H1 in oocytes, which is replaced with a specific histone H1 variant whose function remains elusive. Moreover, the histone H4 acetylation pattern changes during oogenesis, whereby the levels of H4K8ac and H4K12ac decrease as the oocytes mature, while that of H4K16ac increases (Figure 2.1). Interestingly, HDAC1 and 2 are important regulators of oogenesis through gene repression. While HDAC2 is essential in oocyte development, HDAC1 is more responsible for cell-cycle regulation and zygotic development (29,30). In contrast, SIRT1 deficiency does not seem to alter oocyte production in female mice (31).
Epigenetic modulation: Research progress on histone acetylation levels in major depressive disorders
Published in Journal of Drug Targeting, 2023
Yuan Meng, Juan Du, Ning Liu, Yuanyuan Qiang, Lifei Xiao, Xiaobing Lan, Lin Ma, Jiamei Yang, Jianqiang Yu, Guangyuan Lu
Many class I HDACs selective inhibitors and HDACs broad-spectrum inhibitors have been identified and are currently used in anti-tumour research because of their growth-inhibiting effect [53]. The functional importance of abnormally overexpressed HDACs varies substantially depending on the specific subtype. Class I HDACs generally promote cell proliferation; furthermore, both HDAC1 and HDAC2 inhibit apoptosis in cancer cells. HDAC4, 6, 9, and 10 are closely linked to cancer angiogenesis, and class IIb HDACs HDAC6 and 10, together with HDAC3, 4, 5, and 8, hinder differentiation. Thus, HDACis targeting proliferation, differentiation, angiogenesis, and migration can be developed as potential cancer therapeutic strategies. To date, four HDACis have been approved by the US Food and Drug Administration and several others are in clinical trials [54], including suberoylanilide hydroxamic acid (SAHA) and specific HDACis (Table 2). Due to the complex relationship between HDACs and various diseases, these broad-spectrum HDACis act on many targets and are potentially toxic, with some reportedly presenting certain neurotoxicity and cardiotoxicity. Conversely, selective inhibitors have relatively safe and broad therapeutic prospects, and the discovery of selective HDACis with fewer side effects is a current research focus.
Relationship of digit ratio with sexual steroid hormone receptor related genes - single nucleotide polymorphisms in a sample from Northern China
Published in Annals of Human Biology, 2023
Jie Dang, Chengfeng Ma, Fan Li, Jing Zhang, Yuan Wang, Liang Peng, Zhenghao Huo, Hong Lu, Zhanbing Ma
Furthermore, HaploReg prediction revealed that rs12702407 fell into the DNase peak region and the region of proteins bound, including PAX5C20, CEBPB, HDAC2, HEY1, HNF4A, HNF4G, and POL2. These proteins are crucial regulators of mammalian gene expression. Among them, HDAC2 is an important methylated epigenetic modifier and is involved in gene expression regulation through binding to the promoter or enhancer element of GPER1. It may affect GPER1 gene expression through epigenetic modifications. Meanwhile, the change from allele G to A of rs12702407 remarkably affected the CHD2 motif binding according to HaploReg, which might subsequently influence chromatin conformation statuses and may regulate the GPER1 expression in muscle. Another important gene, CEBPB, regulates skeletal stem cell osteogenic differentiation and promotes osteoclastogenesis (Wang J et al. 2022), and may be involved in the formation of finger length ratio.
Cross-talk between energy metabolism and epigenetics during temperature stress response in C2C12 myoblasts
Published in International Journal of Hyperthermia, 2019
Basavaraj Sajjanar, Puntita Siengdee, Nares Trakooljul, Xuan Liu, Claudia Kalbe, Klaus Wimmers, Siriluck Ponsuksili
Histone acetyl transferases (HATs), responsible for acetylation of histone tails, include the three major subtypes p300, Gcn5 and Cbp. The overall expression levels of HATs were increased in response to rising temperatures. Noteworthy, the Gcn5 subtype was significantly upregulated in high thermal stress (41 °C) and downregulated by low temperature stress (35 °C), compared to normothermic condition (Figure 8). Histone deacetylases (HDACs) are responsible for removal of acetyl group from the tails of histones belonging to class I HDACs (Hdac1, Hdac2, Hdac3 and Hdac8) and class II HDACs (Hdac4, Hdac5, Hdac6, Hdac7 and Hdac9). Under low-temperature conditions (35 °C), Hdac2 and Hdac8 (Class I) as well as Hdac4 and Hdac5 (Class II), were significantly downregulated relative to the control cells, while Hdac6 and Hdac7 tended to be upregulated, albeit the latter changes did not reach statistical significance. Hdac8 (Class I) and Hdac7 (Class II) were significantly downregulated in both high-temperature conditions tested (39 °C and 41 °C) (Figure 9). In contrast, Hdac9 was upregulated in the high temperature conditions.