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Redox Biology Aug 2023There are no effective therapeutic targets or strategies that simultaneously inhibit tumour growth and promote cardiac function recovery. Here, we analyzed targets for...
There are no effective therapeutic targets or strategies that simultaneously inhibit tumour growth and promote cardiac function recovery. Here, we analyzed targets for cancer treatments and cardiac repair, with demethylation emerging as a common factor in these candidate lists. As DNA methyltransferase 1 (DNMT1) majorly responds to methylation, a natural compound library is screened, identifying dioscin as a novel agent targeted at DNMT1, widely used for heart diseases. Dioscin was found to reduce DNMT activities and inhibits growth in breast cancer cells. Combined with analyses of RNA-seq and MeDIP-seq, the promoters of antioxidant genes were demethylated after dioscin, recruiting NRF2 and elevating their expression. In Nrf2 knockout mice, the cardiac protection role of dioscin was blocked by Nrf2-loss. Furthermore, in tumour-bearing mice with hypertrophy, dioscin was observed to inhibit tumour growth and alleviate cardiac injury simultaneously. This study is the first to identify dioscin as a novel demethylation agent with dual functions of anti-cancer and cardio-protection.
Topics: Mice; Animals; Recovery of Function; NF-E2-Related Factor 2; Neoplasms; Demethylation; DNA Methylation
PubMed: 37343447
DOI: 10.1016/j.redox.2023.102785 -
Enzyme and Microbial Technology Jun 2021Lignin is an abundant natural plant aromatic biopolymer containing various functional groups that can be exploited for activating lignin for potential commercial... (Review)
Review
Lignin is an abundant natural plant aromatic biopolymer containing various functional groups that can be exploited for activating lignin for potential commercial applications. Applications are hindered due to the presence of a high content of methyl/methoxyl groups that affects reactiveness. Various chemical and enzymatic approaches have been investigated to increase the functionality in transforming lignin. Among these is demethylation/demethoxylation, which increases the potential numbers of vicinal hydroxyl groups for applications as phenol-formaldehyde resins. Although the chemical route to lignin demethylation is well-studied, the biological route is still poorly explored. Bacteria and fungi have the ability to demethylate lignin and lignin-related compounds. Considering that appropriate microorganisms possess the biochemical machinery to demethylate lignin by cleaving O-methyl groups liberating methanol, and modify lignin by increasing the vicinal diol content that allows lignin to substitute for phenol in organic polymer syntheses. Certain bacteria through the actions of specific O-demethylases can modify various lignin-related compounds generating vicinal diols and liberating methanol or formaldehyde as end-products. The enzymes include: cytochrome P-aryl-O-demethylase, monooxygenase, veratrate 3-O-demethylase, DDVA O-demethylase (LigX; lignin-related biphenyl 5,5'-dehydrodivanillate (DDVA)), vanillate O-demethylase, syringate O-demethylase, and tetrahydrofolate-dependent-O-demethylase. Although, the fungal counterparts have not been investigated in depth as in bacteria, O-demethylases, nevertheless, have been reported in demethylating various lignin substrates providing evidence of a fungal enzyme system. Few fungi appear to have the ability to secrete O-demethylases. The fungi can mediate lignin demethylation enzymatically (laccase, lignin peroxidase, manganese peroxidase, O-demethylase), or non-enzymatically in brown-rot fungi through the Fenton reaction. This review discusses details on the aspects of microbial (bacterial and fungal) demethylation of lignins and lignin-model compounds and provides evidence of enzymes identified as specific O-demethylases involved in demethylation.
Topics: Demethylation; Fungi; Laccase; Lignin; Oxidation-Reduction
PubMed: 33992403
DOI: 10.1016/j.enzmictec.2021.109780 -
Science (New York, N.Y.) Dec 2022Active DNA demethylation maintains enhancer activity in nonproliferating cells but can damage DNA.
Active DNA demethylation maintains enhancer activity in nonproliferating cells but can damage DNA.
Topics: DNA Demethylation; Macrophages; Neurons; Enhancer Elements, Genetic; Humans; DNA Breaks, Single-Stranded
PubMed: 36454845
DOI: 10.1126/science.adf3171 -
Essays in Biochemistry Dec 2019DNA methylation is an essential DNA modification that plays a crucial role in genome regulation during differentiation and development, and is disrupted in a range of... (Review)
Review
DNA methylation is an essential DNA modification that plays a crucial role in genome regulation during differentiation and development, and is disrupted in a range of disease states. The recent development of CRISPR/catalytically dead CRISPR/Cas9 (dCas9)-based targeted DNA methylation editing tools has enabled new insights into the roles and functional relevance of this modification, including its importance at regulatory regions and the role of aberrant methylation in various diseases. However, while these tools are advancing our ability to understand and manipulate this regulatory layer of the genome, they still possess a variety of limitations in efficacy, implementation, and targeting specificity. Effective targeted DNA methylation editing will continue to advance our fundamental understanding of the role of this modification in different genomic and cellular contexts, and further improvements may enable more accurate disease modeling and possible future treatments. In this review, we discuss strategies, considerations, and future directions for targeted DNA methylation editing.
Topics: Animals; Bacterial Proteins; CRISPR-Associated Protein 9; CRISPR-Cas Systems; DNA; DNA Demethylation; DNA Methylation; Epigenomics; Gene Editing; Humans; Streptococcus pyogenes
PubMed: 31724704
DOI: 10.1042/EBC20190029 -
Advances in Experimental Medicine and... 2023Epigenetics has major impact on normal development and pathogenesis. Regulation of histone methylation on lysine and arginine residues is a major epigenetic mechanism...
Epigenetics has major impact on normal development and pathogenesis. Regulation of histone methylation on lysine and arginine residues is a major epigenetic mechanism and affects various processes including transcription and DNA repair. Histone lysine methylation is reversible and is added by histone lysine methyltransferases and removed by histone lysine demethylases. As these enzymes are also capable of writing or erasing lysine modifications on non-histone substrates, they were renamed to lysine demethylases (KDMs) in 2007. Since the discovery of the first lysine demethylase LSD1/KDM1A in 2004, eight more subfamilies of lysine demethylases have been identified and further characterized. The joint efforts by academia and industry have led to the development of potent and specific small molecule inhibitors of KDMs for treatment of cancer and several other diseases. Some of these inhibitors have already entered clinical trials since 2013, less than 10 years after the discovery of the first KDM. In this chapter, we briefly summarize the major roles of histone demethylases in normal development and human diseases and the efforts to target these enzymes to treat various diseases.
Topics: Humans; Histones; Lysine; Arginine; DNA Repair; Demethylation; Histone Demethylases
PubMed: 37751133
DOI: 10.1007/978-3-031-38176-8_1 -
Cancer Research Communications Aug 2023Epigenetic reprogramming, mediated by genomic alterations and dysregulation of histone reader and writer proteins, plays a critical role in driving prostate cancer...
UNLABELLED
Epigenetic reprogramming, mediated by genomic alterations and dysregulation of histone reader and writer proteins, plays a critical role in driving prostate cancer progression and treatment resistance. However, the specific function and regulation of EHMT1 (also known as GLP) and EHMT2 (also known as G9A), well-known histone 3 lysine 9 methyltransferases, in prostate cancer progression remain poorly understood. Through comprehensive investigations, we discovered that both EHMT1 and EHMT2 proteins have the ability to activate oncogenic transcription programs in prostate cancer cells. Silencing EHMT1/2 or targeting their enzymatic activity with small-molecule inhibitors can markedly decrease prostate cancer cell proliferation and metastasis and . In-depth analysis of posttranslational modifications of EHMT1 protein revealed the presence of methylation at lysine 450 and 451 residues in multiple prostate cancer models. Notably, we found that lysine 450 can be demethylated by LSD1. Strikingly, concurrent demethylation of both lysine residues resulted in a rapid and profound expansion of EHMT1's chromatin binding capacity, enabling EHMT1 to reprogram the transcription networks in prostate cancer cells and activate oncogenic signaling pathways. Overall, our studies provide valuable molecular insights into the activity and function of EHMT proteins during prostate cancer progression. Moreover, we propose that the dual-lysine demethylation of EHMT1 acts as a critical molecular switch, triggering the induction of oncogenic transcriptional reprogramming in prostate cancer cells. These findings highlight the potential of targeting EHMT1/2 and their demethylation processes as promising therapeutic strategies for combating prostate cancer progression and overcoming treatment resistance.
SIGNIFICANCE
In this study, we demonstrate that EHMT1 and EHMT2 proteins drive prostate cancer development by transcriptionally activating multiple oncogenic pathways. Mechanistically, the chromatin binding of EHMT1 is significantly expanded through demethylation of both lysine 450 and 451 residues, which can serve as a critical molecular switch to induce oncogenic transcriptional reprogramming in prostate cancer cells.
Topics: Male; Humans; Lysine; Histones; Neoplastic Processes; Prostatic Neoplasms; Prostatic Hyperplasia; Histone-Lysine N-Methyltransferase; Chromatin; Demethylation; Histocompatibility Antigens
PubMed: 37663929
DOI: 10.1158/2767-9764.CRC-23-0208 -
Advances in Experimental Medicine and... 2022The regulation of the genome relies on the overlying epigenome to instruct, define, and restrict the activities of cellular differentiation and growth integral to...
The regulation of the genome relies on the overlying epigenome to instruct, define, and restrict the activities of cellular differentiation and growth integral to embryonic development, as well as defining the key activities of terminally differentiated cell types. These instructions are positioned as readers, writers, and erasers in their functional roles. Among the sizeable repertoire of epigenetic instructions, DNA methylation is perhaps the best understood process. In mammals, multiple cycles of reprogramming, the addition and removal of DNA methylation coupled with modulation of chromatin post-translational modifications (PMTs), constitute critical phases when the developing embryo must negotiate lineage specification and commitment events which serve to canalise development. During these reprogramming events the DNA methylation instruction is often removed, thereby allowing a change in developmental restriction, resulting in a return to a more plastic and pluripotent state. Thus, in germline reprogramming, DNA demethylation is essential in order to give rise to fully functional gametes which are inherited across generations and poised to restore totipotency. A similar return to a less differentiated state can also be achieved experimentally. DNA methylation constitutes one of the significant barriers to erroneous induced pluripotency, and loss of DNA methylation is a prerequisite for the generation of induced pluripotent stem cells (iPSCs). Taking fully differentiated cells, such as skin fibroblast cells or peripheral blood cells, and turning back the developmental clock by generating iPSCs constituted a technological breakthrough in 2006, offering unprecedented promise in precision regenerative medicine. In this chapter, I will explore mechanistic possibilities for DNA demethylation in the context of natural and experimentally induced epigenetic reprogramming. The balance of the maintenance of DNA methylation as a heritable mark together with its potential for timely removal is essential for lifelong health and may be key in our understanding of aging and the potential to limit or reverse that process.
Topics: Animals; DNA Demethylation; Cellular Reprogramming; DNA Methylation; Embryonic Development; Embryo, Mammalian; Mammals; Epigenesis, Genetic
PubMed: 36350512
DOI: 10.1007/978-3-031-11454-0_9 -
Cancer Research Jul 2021RNA -methyladenosine (mA) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA mA is regulated by the RNA mA methyltransferases... (Review)
Review
RNA -methyladenosine (mA) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA mA is regulated by the RNA mA methyltransferases methyltransferase-like 3 (METTL3), METTL14, and METTL16 (writers), demethylases FTO and ALKBH5 (erasers), and binding proteins YTHDC1-2, YTHDF1-3, IGF2BP1-3, and SND1 (readers). These RNA mA modification proteins are frequently upregulated or downregulated in human cancer tissues and are often associated with poor patient prognosis. By modulating pre-mRNA splicing, mRNA nuclear export, decay, stability, and translation of oncogenic and tumor suppressive transcripts, RNA mA modification proteins regulate cancer cell proliferation, survival, migration, invasion, tumor initiation, progression, metastasis, and sensitivity to anticancer therapies. Importantly, small-molecule activators of METTL3, as well as inhibitors of METTL3, FTO, ALKBH5, and IGF2BP1 have recently been identified and have shown considerable anticancer effects when administered alone or in combination with other anticancer agents, both and in mouse models of human cancers. Future compound screening and design of more potent and selective RNA mA modification protein inhibitors and activators are expected to provide novel anticancer agents, appropriate for clinical trials in patients with cancer tissues harboring aberrant RNA mA modification protein expression or RNA mA modification protein-induced resistance to cancer therapy.
Topics: Adenosine; Animals; Demethylation; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Methylation; Neoplasms; RNA
PubMed: 34228629
DOI: 10.1158/0008-5472.CAN-20-4107 -
Archives of Biochemistry and Biophysics Aug 2020Neutrophil extracellular traps (NETs) occur during the development of autoimmune diseases, cancer and diabetes. A novel form of cell death that is induced by NETs is...
Neutrophil extracellular traps (NETs) occur during the development of autoimmune diseases, cancer and diabetes. A novel form of cell death that is induced by NETs is called NETosis. Although these diseases are known to have an epigenetic component, epigenetic regulation of NETosis has not previously been explored. In the present study, we investigated the effects of epigenetic change, especially DNA demethylation, on NETosis in neutrophil-like cells differentiated from HL-60 cells, which were incubated for 72 h in the presence of 1.25% DMSO. DMSO-differentiated neutrophil-like cells tended to have increased methylation of genomic DNA. NETosis in the neutrophil-like cells was induced by the treatment with A23187, calcium ionophore, and increased by the addition of the DNMT inhibitor 5-azacytidine (Aza) during differentiation. Interestingly, Aza-stimulated neutrophil-like cell induced NETosis without treatment with A23187. Although reactive oxygen species (ROS), especially superoxide and hypochlorous acid, are important in NETosis induction, treatment with Aza decreased production of ROS, while mitochondria ROS scavenger tended to decrease Aza-induced NETosis. Moreover, the genomic DNA in Aza-stimulated neutrophil-like cell was demethylated, and the expression of peptidylarginine deiminase4 (PAD4) and citrullinated histone H3 (R2+R8+R17) was increased, but myeloperoxidase expression was unaffected. Additionally, PAD4 inhibition tended to decrease Aza-induced NETosis. The DNA demethylation induced by the DNMT inhibitor in neutrophil-like cells enhanced spontaneous NETosis through increasing PAD4 expression and histone citrullination. This study establishes a relationship between NETosis and epigenetics for the first time, and indicates that various diseases implicated to have an epigenetic component might be exacerbated by excessive NETosis also under epigenetic control.
Topics: Cell Death; Cell Differentiation; DNA; DNA Demethylation; Epigenesis, Genetic; Extracellular Traps; HL-60 Cells; Humans; Neutrophils
PubMed: 32561201
DOI: 10.1016/j.abb.2020.108465 -
Oncotarget Oct 2016Protein arginine methylation is a common post-translational modification involved in numerous cellular processes including transcription, DNA repair, mRNA splicing and... (Review)
Review
Protein arginine methylation is a common post-translational modification involved in numerous cellular processes including transcription, DNA repair, mRNA splicing and signal transduction. Currently, there are nine known members of the protein arginine methyltransferase (PRMT) family, but only one arginine demethylase has been identified, namely the Jumonji domain-containing 6 (JMJD6). Although its demethylase activity was initially challenged, its dual activity as an arginine demethylase and a lysine hydroxylase is now recognized. Interestingly, a growing number of substrates for arginine methylation and demethylation play key roles in tumorigenesis. Though alterations in the sequence of these enzymes have not been identified in cancer, their overexpression is associated with various cancers, suggesting that they could constitute targets for therapeutic strategies. In this review, we present the recent knowledge of the involvement of PRMTs and JMJD6 in tumorigenesis.
Topics: Arginine; Demethylation; Humans; Jumonji Domain-Containing Histone Demethylases; Methylation; Neoplasms; Protein Processing, Post-Translational
PubMed: 27556302
DOI: 10.18632/oncotarget.11376