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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).
Pathophysiological significance of Stim1 mutation in sympathetic response to stress and cardiovascular phenotypes in SHRSP/Izm: In vivo evaluation by creation of a novel gene knock-in rat using CRISPR/Cas9
Published in Clinical and Experimental Hypertension, 2021
Batbayar Odongoo, Hiroki Ohara, Davis Ngarashi, Takehito Kaneko, Yayoi Kunihiro, Tomoji Mashimo, Toru Nabika
This experiment was performed as described by Yoshimi et al. (35) and the results obtained are summarized in Table 1. Briefly, potential off-target sites in the rat genome (rn5) were identified using the CRISPR design tool (crispr.mit.edu). In the panel obtained, seven high-ranked potential sites at 0.6 Hit Score and over were sequenced in 3 progenitor homozygous rats (♂1 and ♀2, also see Results). All seven sites were located in intergenic or intronic regions. In addition, one exonic site identified in Mta2 was analyzed to exclude the possibility of nonspecific modifications in this gene. The primer sequences used for PCR and direct sequencing are listed in Table 1.
Dysregulated translational factors and epigenetic regulations orchestrate in B cells contributing to autoimmune diseases
Published in International Reviews of Immunology, 2023
Ming Yang, Ping Yi, Jiao Jiang, Ming Zhao, Haijing Wu, Qianjin Lu
In pro-B cells, epigenetic regulations contribute to Igh gene recombination. For instance, histone methyltransferase (HMT) Setd2, exclusively catalyzing histone H3 trimethylated at lysine-36 (H3K36me3) that serves as a crucial epigenetic modification in DNA repair pathways, is essential for V(D)J recombination of Igh gene [83]. Similarly, enhancer of zest 2 (Ezh2) mediating H3 methylation, a subunit of the polycomb repressive complex 2 (PRC2), could regulate Igh gene rearrangement in early murine B cell development [84]. Meanwhile, the transition of pro-B cells to pre-B cells is regulated by ten-eleven translocation (Tet) enzymes Tet2 and Tet3, which could promote demethylation and chromatin accessibility of Igk enhancers, with the cooperation of IRF4 [85]. The chromo-domain-helicase-DNA binding protein 4 (CHD4), an element of the nucleosome remodeling and histone deacetylase (NuRD) complex, has been proven essential for pre-B cell maintenance and development, as well as B cell proliferation via repressing p53 [86]. Besides, the Igk gene transcription and rearrangement in pre-B cells are regulated by PU.1 through binding the promoter region and depositing H3K4me1 in pro-/pre-B cells, generating BCR diversity [87]. Finally, MTA2/NuRD complex binds Aiolos/Ikaros target genes and cooperates with OcaB to promote the transition from pre-B cells to immature B cells through repressing Igll1 and VpreB1 expression by H3K27 deacetylation [88]. The generation of BCR in immature B cells is epigenetically regulated by EBF1 and E47, which demethylate the promoter of Cd79a encoding Igα element of BCR, and enhance the activation of Cd79a by Pax5 [89]. Furthermore, miR-125b appears silenced epigenetically in normal B cell-lineage development, and dysregulated miR-125b inhibits B cell egress from bone marrow into peripheral lymphoid tissues by suppressing sphingosine-1-phosphate receptor 1 (S1PR1), as well as induces pre-B cell leukemia [90]. The epigenetic alterations implicated in B cell lymphopoiesis are shown in Figure 1.
The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy
Published in Expert Opinion on Drug Discovery, 2019
Najah Albadari, Shanshan Deng, Wei Li
Many posttranslational acetylation and deacetylation events have been reported to play a role in regulating both HIF-1/2α protein stability and transcriptional activity. However, conflicting data bring into the question about the foundations of these regulation mechanisms and their roles in HIF-1/2α regulation require clarification. Multiple sites of the HIF-1α protein can be modified by lysine acetylation leading to different downstream effects. For example, acetylation within the ODDD is related to the pVHL-dependent HIF-1α degradation where Jeong et al. showed that pVHL binding is also promoted by acetylation of lysine (K532) residue of HIF-1α by direct binding of Arrest defective-1 (ARD1), a protein acetyltransferase [55]. Thereafter, the ubiquitinated HIF-1α serves as the signal for degradation mediated by the 26S proteasome. However, the acetylation function of ARD1 is counteracted by the action of Metastasis-associated protein 1 (MTA1), where MTA1 induces the deacetylation of HIF-1α at K532R by increasing the expression of Histone deacetylase 1 (HDAC1) and thus enhances the transcriptional activity and stability of HIF-1α protein. In addition, the expression of MTA1 is strongly induced under hypoxic conditions and it is physically associated with HIF-1α when they are co-expressed [56]. Therefore, both MTA1 and HIF-1α are expected to have important roles in tumor metastasis and progression. Similarly, Zhu et al. showed that Metastasis-associated protein 2 (MTA2), another member of the MTA family, deacetylates HIF-1α and enhances its stability through interacting with HDAC1 in pancreatic carcinoma [57]. Yet, Arnesen et al. and Murray-Rust et al. reported that K532R mutation did not affect the interaction between the HIF-1α ODDD and human ARD1 (hARD1), and they concluded that hARD1 did not acetylate and destabilize HIF-1α [58]. Moreover, Fisher et al. showed that inhibition and overexpression of ARD1 did not affect basal HIF-1α levels or its response to hypoxia [59]. Whereas acetylations of lysine (K709) and lysine (K674) in the carboxy-terminal region of HIF-1α are related to HIF-1α/p300 interaction and HIF-1 transactivation. For example, Geng et al. demonstrated that p300, a component of the HIF-1 transcriptional complex, stabilizes HIF-1α via acetylating lysine (K709) residue in both normal and hypoxic conditions, and they showed that this acetylation is opposed by HDAC1 [60]. However, K674 in HIF-1α was shown to be acetylated primarily by the CBP/p300 -associated factor (PCAF) leading to the increase of HIF-1α protein levels and binding of p300 [61]. Moreover, in the same study, Lim et al. showed that Sirtuin 1 (SIRT1), a NAD-dependent deacetylase, binds to HIF-1α, deacetylates it at K674 position, blocks p300 recruitment and consequently represses HIF-1 target genes. Conversely, Dioum et al. and Chen et al. demonstrated that HIF-2α can be acetylated at K385, K685, and K741 positions within its C terminus by CBP and selectively deacetylated by SIRT1 to augment HIF-2 signaling [62,63].