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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
The first family of HATs are known as general control nonderepressible-5 (GCN-5) related N-acetyltransferase (GNATs), represented by GCN-5 and p300/CREB binding protein (CBP)-associated factor (PCAF). The second family of HATs are p300/CBP, represented by p300 and CBP, while the third family is composed of MYST histone acetyltransferases, named after its four founding members MOZ, Ybf2 (Sas3), Sas2 and Tip60. The MYST family includes trans-activator of transcription (TAT) interacting protein—60 (TIP60) and monocytic leukemia zinc finger protein (Figure 8.1). Unlike Type-A HATs, the Type-B HATs are cytoplasmic and catalyze the acetylation of newly synthesized histones before they form nucleosomal complexes (Figure 8.1A) (Roth et al., 2001). Type-B HATs lack bromodomain, as they are primarily involved in recognizing non-acetylated lysine residues in the histones (Roth et al., 2001).
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Another example of a small-molecule transcription factor inhibitor is trabectedin (YondelisTM) which inhibits NF-Y/PCAF. It was approved in 2015 by the FDA for the treatment of two subtypes of soft-tissue sarcomas, liposarcoma, and leiomyosarcoma.
Targeting Notch Pathways
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Jennifer O’Neil, A. Thomas Look
Notch is synthesized in the endoplasmic reticulum and is transported to the Golgi network where it is posttranslationally modified. A proteolytic clevage (S1) separates the extracellular portion of the protein from the intracellular form. These two parts of Notch then form a heterodimer that is transported to the cell membrane. Binding of Notch ligands, such as Delta and Serrate, initiates a series of additional proteolytic cleavages in Notch. The last of these cleavages, which is catalyzed by γ-secretase, results in the release of the Notch intracellular domain (NICD) permitting it to translocate to the nucleus and form part of a multiprotein complex. The NICD interacts with the DNA-binding protein CSL, displaces compressors and recruits coactivators, thereby converting CSL from a repressor to activator of gene transcription (Fig. 1). Structural studies have demonstrated that the interaction between the Ankyrin domain of Notch 1 and the Rel-homology domain of CSL creates a binding site for the Mamll Notch coactivator that recruits other coactivators such as p300 and PCAF (5).
Prolactin activates IRF1 and leads to altered balance of histone acetylation: Implications for systemic lupus erythematosus
Published in Modern Rheumatology, 2020
Yiu Tak Leung, Kelly Maurer, Li Song, Jake Convissar, Kathleen E. Sullivan
We investigated the expression of HATs and HDACs after chronic PRL treatment directly. We found increases of 2- to 3-fold in transcript levels of PCAF, CBP and p300. ATF2 and GCN5 had modest (but statistically significant) increases in expression at 48 h. These proteins are all notable in that they were previously shown to have protein-protein interactions with IRF1 under IFNα stimulation [47], suggesting a possible autocrine regulatory pathway. In our model, chronic PRL leads to increased IRF1 and increased HAT activity. Indeed, IRF1 has been described as part of a complex that includes PCAF, CBP/p300 and GCN5 [60,61] and IRF1 can recruit this complex for H4 acetylation [60]. This recruits additional genes for transcriptional activation and may contribute to the expression of the interferon signature genes, a set of genes that is refractory to acute PRL but activated with chronic PRL.
TiO2 nanotubes regulate histone acetylation through F-actin to induce the osteogenic differentiation of BMSCs
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2021
Yanchang Liu, Zhicheng Tong, Chen Wang, Runzhi Xia, Huiwu Li, Haoran Yu, Juehua Jing, Wendan Cheng
Histone acetyltransferase is a type of protease that plays an important role in chromosome structural modification and gene expression regulation [21]. The acetylation of histones facilitates the dissociation of DNA and histone octamers and relaxes the nucleosome structure. So that various transcription factors and cooperative transcription factors can specifically bind to DNA binding sites and activate gene transcription [22]. In the nucleus, the processes of histone acetylation and histone deacetylation are in dynamic equilibrium, and are jointly regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC). HAT transfers the acetyl group of acetyl-CoA to specific lysine residues at the amino terminal of histones. HDAC deacetylates histones and binds tightly with negatively charged DNA. The chromatin is dense and curled and gene transcription is inhibited [22]. More importantly, HAT plays an important regulatory role in promoting bone differentiation. Kim et al. demonstrated that the vitamin D receptor can recruit CBP and p300 to the promoters of Cyp and Opn. It can then be combined with 1,25-dihydroxyvitamin D3 to cause histone H4 acetylation in intact osteoblasts [23]. The study by Zhang et al. proved that PCAF is also related to the osteogenesis of MSC. They can induce osteogenesis by increasing the expression level of Smad signals. At the same time, the expression of PCAF increased significantly. This stimulates the expression of BMP pathway genes by increasing the acetylation level of PCAF’s target (histone H3K9) [31]. In order to explore the effect of TiO2 nanotubes on HAT in BMSCs, we screened six enzymes in the HATs family and found that only the expression level of GCN5 steadily increased over time. The results suggested that TiO2 nanotubes may have a specific regulatory relationship with GCN5.
The participation of non-canonical autophagic proteins in the autophagy process and their potential as therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2023
Yiming Yin, Yourong Zhou, Xiaochun Yang, Zhifei Xu, Bo Yang, Peihua Luo, Hao Yan, Qiaojun He
PCAF, also known as lysine acetyltransferase 2B (KAT2B), is a histone acetyltransferase that could acetylate lysine 14 of Histone H3 and it regulates transcriptional activity by directly binding to sequence-specific DNA-binding factors [83–85].