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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
For example, the nucleosome remodeling and histone deacetylase NuRD complex contain seven proteins that consists of HDAC1, HDAC2, RbAp46, RbAp48, Mi2, metastasis-associated protein 2 (MTA2) and methyl-CpG-binding domain protein 3 (MBD3) (Basta and Rauchman, 2015). Whereas MTA2 modulates the enzymatic activity of the histone deacetylase core complex, the MBD3 mediates the association of MTA2 with the core histone deacetylase complex. However, MBD3, although closely related to methylated DNA-binding MBD2 (methyl-CpG-binding domain protein 2), does not directly bind methylated DNA. MBD2 interacts with the NuRD complex and directs the complex to methylated DNA (Kupis et al., 2016). NuRD protein is known to silence the expression of genes through DNA methylation (Kupis et al., 2016). A separate study showed that the interaction between HDAC3 and silencing mediator for retinoid and thyroid hormone receptors/nuclear receptor co-repressor (SMRT/NCoR) stimulates HDAC3 enzyme, thereby reducing the expression of target genes (Guenther et al., 2001).
A Short Introduction to DNA Methylation
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
Transcription may be affected by DNA methylation in several ways (Figure 1.6). First, the binding of transcriptional activators such as Sp1 and Myc may be inhibited directly by the methylated DNA through sterical hindrance, while other transcription factors especially homeodomain transcription factors are attracted by methylated target recognition sequences (24–26). Methylation of CpG sites in a target sequence can thereby lead to change in transcription factor occupancy at the same sequence and activation of tissue-specific genes (27). Second, methylated DNA is bound by specific methyl-CpG binding domain (MBD1, MBD2, and MBD4) proteins or methyl-CpG binding proteins (MeCP2) as well as proteins of the Kaiso family (12,28,29). They recruit transcriptional co-repressors such as histone deacetylating complexes, polycomb proteins and chromatin remodeling complexes, thereby establishing a repressive closed chromatin configuration (Figure 1.6). Mbd3 binds specifically hydroxymethylated cytosines.
MUC1-C integrates type II interferon and chromatin remodeling pathways in immunosuppression of prostate cancer
Published in OncoImmunology, 2022
Masayuki Hagiwara, Atsushi Fushimi, Atrayee Bhattacharya, Nami Yamashita, Yoshihiro Morimoto, Mototsugu Oya, Henry G. Withers, Qiang Hu, Tao Liu, Song Liu, Kwok K. Wong, Mark D. Long, Donald Kufe
While performing these experiments, we recognized that MUC1-C is also playing a role in the posttranscriptional regulation of IFNGR1 expression. In this regard, other work had demonstrated that the FBXW7 ubiquitin ligase promotes degradation of the IFNGR1 protein.45 Those studies showed that the ELF5 TF induced FBXW7 expression and in turn IFNGR1 destabilization.45 There is no known link between MUC1-C and the regulation of FBXW7. MUC1-C activates the NuRD complex, which includes MTA1 and MBD3, in suppressing gene expression46 and has been linked to the regulation of FBXW7 transcription.67 We found that MUC1-C downregulates FBXW7 by a mechanism involving MTA1 and MBD3. MUC1-C, MTA1 and MBD3 were necessary for suppression of FBXW7 and, as a result, stabilization of the IFNGR1 protein (Figure 9). Taken together with the effects of MUC1-C on IFNGR1 transcription, these findings uncovered another previously unrecognized MUC1-C-driven pathway that increases IFNGR1 expression by a posttranscriptional mechanism. Stimulation of IFNGR1 by IFN-γ activates the downstream STAT1 and IRF1 effectors of the type II IFN pathway. Consistent with MUC1-C-induced upregulation of IFNGR1, we found that MUC1 is associated with STAT1 and IRF1 expression in CRPC/NEPC tumors (Figure 9). In addition, silencing MUC1-C, MTA1 and MBD3 in CRPC cells decreased chromatin accessibility and expression of STAT1 and IRF1, indicating that MUC1-C is necessary for activation of the IFNGR1→STAT1/IRF1 pathway (Figure 9).
Emerging DNA methylation inhibitors for cancer therapy: challenges and prospects
Published in Expert Review of Precision Medicine and Drug Development, 2019
Aurora Gonzalez-Fierro, Alfonso Dueñas-González
Abnormal DNA methylation signals may contribute to disease, and the reversible nature of epigenetic alterations makes the DNA methylation machinery an exciting therapeutic target including DNMTs, tet proteins as well as activation-induced cytidine deaminase (AID) protein [34]. In addition, methyl-CpG-binding domain (MBD) proteins which ‘read’ and interpret the methylation moieties on DNA, and are critical mediators of many epigenetic processes, may also targetable. These include at least MBD1, MBD2, MBD3, MBD4, and MeCP2 [35].
Association between MeCP2 and Smad7 in the pathogenesis and development of pathological scars
Published in Journal of Plastic Surgery and Hand Surgery, 2021
Dan Li, E. Yang, Juan Zhao, Hengshu Zhang
DNA methylation plays an essential role in the evolution of mammals. The hypermethylated state of gene promoter inhibits gene transcription, while the hypomethylated state can induce gene activation and expression [16]. Methylated binding proteins, such as MeCP2, MBD1, MBD2, MBD3 and MBD4, are a class of proteins that bind to methylated-CpG dinucleotides. Previous studies demonstrated that MeCP2, MBD1 and MBD2 could bind to the hypermethylated promoter to inhibit gene transcription [12], and the mRNA expression of MeCP2 was upregulated in chronic hepatitis B [17], pulmonary fibrosis [18] and scleroderma [19]. During the process of organ fibrosis, MeCP2 acts as a transcriptional repressor to inhibit the function of negative regulators of fibrogenesis, thereby promoting tissue fibrosis in various organs. In the lung fibrosis model, when the expression of MeCP2 was inhibited, the expression levels of fibrosis-related cytokines were significantly decreased, and the severity of fibrosis was also reduced [20]. This indicates that DNA methylation acts as an inhibitory regulator in the TGF-β/Smad signaling pathway, and is involved in scar formation after wound healing. Based on the commonality of epigenetic modifications of cancer and fibrosis [21], DNA hypermethylation of specific genes may contribute to the occurrence of fibrosis. In this study, Western blot and real-time polymerase chain reaction (RT-PCR) experiments showed that MeCP2 expression was significantly increased in keloid and hypertrophic scars, which is consistent with the increased expression of MeCP2 in cirrhotic fibroblasts. A significant difference in MeCP2 levels was also observed in hypertrophic scars at different growth stages. Compared with the regression and maturity stages, MeCP2 expression was significantly upregulated during the early growth and hyperplasia stages. Overall, these results suggest that MeCP2 may serve as a new target for inhibiting scar formation.