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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).
Schwannomatosis
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The LZTR1 gene is situated approximately 3 Mb and 9 Mb centromeric to SMARCB1 and NF2, respectively, on chromosome 22q11.21, and encodes a member of the BTB/POZ superfamily of proteins, which is present exclusively in the Golgi network and participates in multiple cellular processes (e.g., regulation of chromatin conformation and cell cycle). As a likely tumor suppressor gene, LZTR1 may share a functional link with SMARCB1 through nuclear receptor corepressor (N-CoR) interactions [9]. In up to 80% of SMARCB1 mutation–negative schwannomatosis cases, LZTR1 loss of function mutations (missense, splice site, nonsense, or frameshift) are identified across nearly all exons. Similar to SMARCB1-related schwannomatosis, schwannoma patients with LZTR1 mutation also harbor somatic NF2 mutations. Besides schwannomatosis, biallelic LZTR1 mutations have been identified in glioblastoma [7,16].
Retinoic acid signaling in spermatogenesis and male (in)fertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Dario Santos, Rita Payan-Carreira
According to the canonical model of gene regulation by RARs (Figure 7.1), in the absence of RA, the DNA-bound RAR subtype represses target gene expression through the recruitment of co-repressors such as nuclear receptor co-repressor (NCoR) or silencing mediator of RA and thyroid hormone receptor (SMRT). Several studies suggested that SMRT would be the RAR-favored co-repressor (36,37), which serves as a molecular adaptor recruiting histone deacetylase (HDAT) (38). The co-repressor complex deacetylates lysine residues in the N-terminal tails of histones and induces chromatin condensation and repressed state over the target promoter (39,40). Binding of RA induces a conformational change of the RAR/RXR heterodimer that results in the release of co-repressors and creates a new interaction surface for co-activators, which include p160 subfamily of steroid receptor coactivators (SRCs), namely, SRC-1, SRC-2 and SRC-3 (29,41). The p160 coactivators have intrinsic histone acetyltransferase (HAT) activity and acetylate several lysine residues in H3 and H4, initiating gene transcription (42).
Role of bromodomain and extraterminal (BET) proteins in prostate cancer
Published in Expert Opinion on Investigational Drugs, 2023
Adel Mandl, Mark C. Markowski, Michael A. Carducci, Emmanuel S. Antonarakis
Preclinical studies also demonstrated that prostate cancer-specific mutations in SPOP (speckle-type POZ protein), an E3 ubiquitin ligase substrate binding protein commonly mutated in prostate cancer, resulted in impaired degradation of BETs and promoted intrinsic resistance to BET inhibitors both in vitro and in vivo prostate cancer models [64–67]. Another resistance mechanism may be related to deubiquitinating enzyme 3 (DUB3), which binds to BRD4 and promotes its deubiquitination and stabilization. The nuclear receptor corepressor 2 (NCOR2)–histone deacetylase 10 (HDAC10) complex transcriptionally represses the expression of DUB3 [68]. The NCOR2 gene is frequently deleted in CRPC patient specimens, and loss of NCOR2 induces the elevation of DUB3 and BRD4 proteins in PC cells [69]. DUB3-proficient PC cells are resistant to the BET inhibitor JQ1 in vitro and in vivo, but this effect is diminished by DUB3 inhibitory agents [68]. This suggests that DUB3 could be a viable therapeutic target to overcome BET inhibitor resistance.
The claudin–transcription factor signaling pathway
Published in Tissue Barriers, 2021
Importantly, the CLDN6/SFK/PI3K/AKT axis targets the AKT-phosphorylation sites in the RARγ and the estrogen receptor α (ERα) and stimulates their activities, thereby regulating the expression of respective target genes. This conclusion was drawn from the following results: (1) the CLDN6-induced cellular events were hindered in three distinct F9:Rxra–/–:Rarg–/–:Cldn6 cell lines, despite SFKs being activated; (2) AKT formed a complex with either RXRα/RARγ or ERα; and (3) characterization of F9:Rxra–/–:Rarg–/–:Cldn6:iRxra-Rarg2S379A (hereafter, “i” means doxycycline-inducible expression of a give gene) and F9:Rxra–/–:Rarg–/–:Cldn6:iRxra-Rarg2S379E cells, as well as MCF-7:ESR1S518E cells, revealed that CLDN6 signaling directs S379 and S518 in mouse RARγ and human ERα, respectively. In addition, CLDN6-provoked RARγS379 phosphorylation in mice resulted in releasing the nuclear receptor corepressor (NCoR) from several retinoic acid response elements (RAREs) of three distinct RA target genes, including Cldn6. Since RXRα/RARγ heterodimer appears to induce Cldn6 gene expression,56,61 the positive loop of the CLDN6–RARγ cascade could contribute not only to triggering but also to the maintenance of CLDN6-initiated cellular events. Intriguingly, the AKT-consensus phosphorylation motifs are conserved in 14 of 48 members of human nuclear receptors, implying the biological relevance of this phosphorylation site.
Class IIa HDACs do not influence beta-cell function under normal or high glucose conditions
Published in Islets, 2019
Jacob McCann, Megan Ellis, Sean L. McGee, Kathryn Aston-Mourney
Class IIa HDACs lack intrinsic HDAC catalytic activity but repress gene expression by associating with the myocyte enhancer factor-2 (MEF2) transcription factors and recruiting a transcriptional corepressor complex to MEF2-dependent genes.1 We have shown that disruption of the Class IIa HDAC corepressor complex (class IIa HDACs HDAC4 and HDAC5 interacting with HDAC3, nuclear receptor corepressor 2 (SMRT) and nuclear receptor corepressor 1 (Ncor)) is a promising therapeutic target to enhance metabolic health in chronic diseases including type 2 diabetes as well as obesity, cardiovascular disease and non-alcoholic fatty liver disease.2,3 This corepressor complex is naturally disrupted in skeletal muscle during exercise due to phosphorylation-dependent nuclear export of HDAC4 and HDAC5.4 Disruption of this complex in skeletal muscle by expressing active site mutants of HDAC4 and HDAC5 (that act in a dominant negative manner), results in increased MEF2-dependent transcription and increased expression of genes involved in several metabolic pathways as well as mitochondrial function.2,4 Therefore, pharmacological targeting of the Class IIa HDAC corepressor complex is a potential therapeutic strategy to enhance metabolic health in chronic diseases. However, while the effect of disrupting this complex in skeletal muscle has been well validated, the effect on the beta-cell is currently unknown. Given that beta-cell function plays such a vital role in type 2 diabetes, it is important that the effects of disrupting the Class IIa HDAC corepressor complex specifically on beta-cells is determined.