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Neuro-oncology May 2022
Topics: DNA; Demethylation; Glioma; Humans; Isocitrate Dehydrogenase; Tretinoin
PubMed: 35239963
DOI: 10.1093/neuonc/noac056 -
Clinical Epigenetics Jul 2022SLC5A7 (solute carrier family 5 member 7), also known as choline transporter 1 (CHT1), is downregulated in colorectal cancer (CRC) and functions as a tumor suppressor....
BACKGROUND
SLC5A7 (solute carrier family 5 member 7), also known as choline transporter 1 (CHT1), is downregulated in colorectal cancer (CRC) and functions as a tumor suppressor. However, the mechanisms underlying the inactivation of SLC5A7 in CRC remain to be elucidated.
RESULTS
In the present study, two broad-spectrum demethylation agents (azacitidine and decitabine) employed to treat CRC cells significantly upregulated SLC5A7 expression. Further results based on the CRC cohort and TCGA database indicated that SLC5A7 promoter methylation inversely correlated with SLC5A7 expression, and the status of SLC5A7 promotor methylation showed a promising prognostic value for patients with CRC. Next, the dCas9-multiGCN4/scFv-TET1CD-based precision demethylation system was constructed, which could significantly and specifically promote SLC5A7 expression in CRC cells through sgRNA targeting the SLC5A7 promoter. Both in vitro and in vivo experiments demonstrated that targeted demethylation of SLC5A7 by dCas9-multiGCN4/scFv-TET1CD-sgSLC5A7 inhibited tumor growth by stabilizing p53 and regulating downstream targets.
CONCLUSIONS
Collectively, DNA promoter methylation caused inactivation of SLC5A7 in CRC, and targeted demethylation of SLC5A7 might be a therapeutic target for CRC and other cancers.
Topics: Azacitidine; Cell Line, Tumor; Colorectal Neoplasms; DNA Methylation; Demethylation; Gene Expression Regulation, Neoplastic; Humans; Promoter Regions, Genetic; Symporters
PubMed: 35858918
DOI: 10.1186/s13148-022-01308-5 -
Epigenomics Mar 2023
Topics: Humans; DNA Demethylation; 5-Methylcytosine; Embryonic Development; DNA Methylation
PubMed: 37191057
DOI: 10.2217/epi-2023-0104 -
Analytical Cellular Pathology... 2018Over the years, the epigenetic landscape has grown increasingly complex. Until recently, methylation of DNA and histones was considered one of the most important... (Review)
Review
Over the years, the epigenetic landscape has grown increasingly complex. Until recently, methylation of DNA and histones was considered one of the most important epigenetic modifications. However, with the discovery of enzymes involved in the demethylation process, several exciting prospects have emerged that focus on the dynamic regulation of methylation and its crucial role in development and disease. An interplay of the methylation-demethylation machinery controls the process of gene expression. Since acute kidney injury (AKI), a major risk factor for chronic kidney disease and death, is characterised by aberrant expression of genes, understanding the dynamics of methylation and demethylation will provide new insights into the intricacies of the disease. Research on epigenetics in AKI has only made its mark in the recent years but has provided compelling evidence that implicates the involvement of methylation and demethylation changes in its pathophysiology. In this review, we explore the role of methylation and demethylation machinery in cellular epigenetic control and further discuss the contribution of methylomic changes and histone modifications to the pathophysiology of AKI.
Topics: Acute Kidney Injury; Animals; DNA Methylation; Demethylation; Epigenesis, Genetic; Humans
PubMed: 30073137
DOI: 10.1155/2018/8764384 -
Cold Spring Harbor Perspectives in... May 2017Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to... (Review)
Review
Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to activate oncogenes and silence of tumor-suppressor genes. Targeting DNA methylation in cancer using DNA hypomethylating drugs reprograms tumor cells to a more normal-like state by affecting multiple pathways, and also sensitizes these cells to chemotherapy and immunotherapy. The first generation hypomethylating drugs azacitidine and decitabine are routinely used for the treatment of myeloid leukemias and a next-generation drug (guadecitabine) is currently in clinical trials. This review will summarize preclinical and clinical data on DNA hypomethylating drugs as a cancer therapy.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Clinical Trials as Topic; DNA Demethylation; Decitabine; Humans; Neoplasms; Tumor Microenvironment
PubMed: 28159832
DOI: 10.1101/cshperspect.a026948 -
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 -
BMC Medicine Apr 2023Helicobacter pylori (H. pylori) infection causes aberrant DNA methylation and contributes to the risk of gastric cancer (GC). Guanine nucleotide-binding protein subunit...
BACKGROUND
Helicobacter pylori (H. pylori) infection causes aberrant DNA methylation and contributes to the risk of gastric cancer (GC). Guanine nucleotide-binding protein subunit beta-4 (GNB4) is involved in various tumorigenic processes. We found an aberrant methylation level of GNB4 in H. pylori-induced GC in our previous bioinformatic analysis; however, its expression and underlying molecular mechanisms are poorly understood.
METHODS
The expression, underlying signaling pathways, and clinical significance of GNB4 were analyzed in a local cohort of 107 patients with GC and several public databases. H. pylori infection was induced in in vitro and in vivo models. Methylation-specific PCR, pyrosequencing, and mass spectrometry analysis were used to detect changes in methylation levels. GNB4, TET1, and YAP1 were overexpressed or knocked down in GC cell lines. We performed gain- and loss-of-function experiments, including CCK-8, EdU, colony formation, transwell migration, and invasion assays. Nude mice were injected with genetically manipulated GC cells, and the growth of xenograft tumors and metastases was measured. Real-time quantitative PCR, western blotting, immunofluorescence, immunohistochemistry, chromatin immunoprecipitation, and co-immunoprecipitation experiments were performed to elucidate the underlying molecular mechanisms.
RESULTS
GNB4 expression was significantly upregulated in GC and correlated with aggressive clinical characteristics and poor prognosis. Increased levels of GNB4 were associated with shorter survival times. Infection with H. pylori strains 26695 and SS1 induced GNB4 mRNA and protein expression in GC cell lines and mice. Additionally, silencing of GNB4 blocked the pro-proliferative, metastatic, and invasive ability of H. pylori in GC cells. H. pylori infection remarkably decreased the methylation level of the GNB4 promoter region, particularly at the CpG#5 site (chr3:179451746-179451745). H. pylori infection upregulated TET1 expression via activation of the NF-κB. TET binds to the GNB4 promoter region which undergoes demethylation modification. Functionally, we identified that GNB4 induced oncogenic behaviors of tumors via the Hippo-YAP1 pathway in both in vitro and in vivo models.
CONCLUSIONS
Our findings demonstrate that H. pylori infection activates the NF-κB-TET1-GNB4 demethylation-YAP1 axis, which may be a potential therapeutic target for GC.
Topics: Humans; Mice; Animals; NF-kappa B; Helicobacter pylori; Mice, Nude; Carcinogenesis; Stomach Neoplasms; Demethylation; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Mixed Function Oxygenases; Proto-Oncogene Proteins; GTP-Binding Protein beta Subunits
PubMed: 37016382
DOI: 10.1186/s12916-023-02842-6 -
European Heart Journal May 2023
Topics: Humans; RNA, Antisense; RNA, Long Noncoding; Ventricular Remodeling; Pericardium; Demethylation; Basic Helix-Loop-Helix Transcription Factors
PubMed: 36928295
DOI: 10.1093/eurheartj/ehad058 -
Nature Communications Mar 2021Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to...
Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its N,2'-O-dimethyladenosine (mA) demethylase activity. While mA is strategically located next to the mG-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates mA level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear mA methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of mA modification in stem-like properties acquisition. FTO-mediated regulation of mA marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the mA modification and its potential adverse consequences for colorectal cancer management.
Topics: Adaptor Proteins, Signal Transducing; Adenosine; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Cell Line, Tumor; Cell Nucleus; Colorectal Neoplasms; Cytoplasm; Demethylation; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Methyltransferases; Nuclear Proteins; RNA, Messenger
PubMed: 33741917
DOI: 10.1038/s41467-021-21758-4 -
Clinical and Translational Medicine Sep 2023Cysteine dioxygenase 1 (CDO1) is frequently methylated, and its expression is decreased in many human cancers including breast cancer (BC). However, the functional and...
BACKGROUND
Cysteine dioxygenase 1 (CDO1) is frequently methylated, and its expression is decreased in many human cancers including breast cancer (BC). However, the functional and mechanistic aspects of CDO1 inactivation in BC are poorly understood, and the diagnostic significance of serum CDO1 methylation remains unclear.
METHODS
We performed bioinformatics analysis of publicly available databases and employed MassARRAY EpiTYPER methylation sequencing technology to identify differentially methylated sites in the CDO1 promoter of BC tissues compared to normal adjacent tissues (NATs). Subsequently, we developed a MethyLight assay using specific primers and probes for these CpG sites to detect the percentage of methylated reference (PMR) of the CDO1 promoter. Furthermore, both LentiCRISPR/dCas9-Tet1CD-based CDO1-targeted demethylation system and CDO1 overexpression strategy were utilized to detect the function and underlying mechanism of CDO1 in BC. Finally, the early diagnostic value of CDO1 as a methylation biomarker in BC serum was evaluated.
RESULTS
CDO1 promoter was hypermethylated in BC tissues, which was related to poor prognosis (p < .05). The CRISPR/dCas9-based targeted demethylation system significantly reduced the PMR of CDO1 promotor and increased CDO1 expression in BC cells. Consequently, this leads to suppression of cell proliferation, migration and invasion. Additionally, we found that CDO1 exerted a tumour suppressor effect by inhibiting the cell cycle, promoting cell apoptosis and ferroptosis. Furthermore, we employed the MethyLight to detect CDO1 PMR in BC serum, and we discovered that serum CDO1 methylation was an effective non-invasive biomarker for early diagnosis of BC.
CONCLUSIONS
CDO1 is hypermethylated and acts as a tumour suppressor gene in BC. Epigenetic editing of abnormal CDO1 methylation could have a crucial role in the clinical treatment and prognosis of BC. Additionally, serum CDO1 methylation holds promise as a valuable biomarker for the early diagnosis and management of BC.
Topics: Humans; Clustered Regularly Interspaced Short Palindromic Repeats; Cysteine Dioxygenase; Apoptosis; Cell Cycle; Demethylation; Neoplasms
PubMed: 37740473
DOI: 10.1002/ctm2.1423