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Endocrine-related Cancer Jul 2019In recent years, cancer genomics has provided new insights into genetic alterations and signaling pathways involved in thyroid cancer. However, the picture of the... (Review)
Review
In recent years, cancer genomics has provided new insights into genetic alterations and signaling pathways involved in thyroid cancer. However, the picture of the molecular landscape is not yet complete. DNA methylation, the most widely studied epigenetic mechanism, is altered in thyroid cancer. Recent technological advances have allowed the identification of novel differentially methylated regions, methylation signatures and potential biomarkers. However, despite recent progress in cataloging methylation alterations in thyroid cancer, many questions remain unanswered. The aim of this review is to comprehensively examine the current knowledge on DNA methylation in thyroid cancer and discuss its potential clinical applications. After providing a general overview of DNA methylation and its dysregulation in cancer, we carefully describe the aberrant methylation changes in thyroid cancer and relate them to methylation patterns, global hypomethylation and gene-specific alterations. We hope this review helps to accelerate the use of the diagnostic, prognostic and therapeutic potential of DNA methylation for the benefit of thyroid cancer patients.
Topics: Antineoplastic Agents; Biomarkers, Tumor; DNA Methylation; Demethylation; Epigenome; Gene Expression Regulation, Neoplastic; Humans; Prognosis; Signal Transduction; Thyroid Neoplasms
PubMed: 31035251
DOI: 10.1530/ERC-19-0093 -
Nature Genetics Sep 2022Transcriptional regulation, which integrates chromatin accessibility, transcription factors and epigenetic modifications, is crucial for establishing and maintaining...
Transcriptional regulation, which integrates chromatin accessibility, transcription factors and epigenetic modifications, is crucial for establishing and maintaining cell identity. The interplay between different epigenetic modifications and its contribution to transcriptional regulation remains elusive. Here, we show that METTL3-mediated RNA N-methyladenosine (mA) formation leads to DNA demethylation in nearby genomic loci in normal and cancer cells, which is mediated by the interaction between mA reader FXR1 and DNA 5-methylcytosine dioxygenase TET1. Upon recognizing RNA mA, FXR1 recruits TET1 to genomic loci to demethylate DNA, leading to reprogrammed chromatin accessibility and gene transcription. Therefore, we have characterized a regulatory mechanism of chromatin accessibility and gene transcription mediated by RNA mA formation coupled with DNA demethylation, highlighting the importance of the crosstalk between RNA mA and DNA modification in physiologic and pathogenic process.
Topics: Chromatin; DNA; DNA Demethylation; DNA Methylation; RNA; Transcription Factors
PubMed: 36071173
DOI: 10.1038/s41588-022-01173-1 -
Science (New York, N.Y.) Jul 2023Methylations on nucleosomal histones play fundamental roles in regulating eukaryotic transcription. Jumonji C domain-containing histone demethylases (JMJs) dynamically...
Methylations on nucleosomal histones play fundamental roles in regulating eukaryotic transcription. Jumonji C domain-containing histone demethylases (JMJs) dynamically control the level of histone methylations. However, how JMJ activity is generally regulated is unknown. We found that the tricarboxylic acid cycle-associated enzyme α-ketoglutarate (α-KG) dehydrogenase (KGDH) entered the nucleus, where it interacted with various JMJs to regulate α-KG-dependent histone demethylations by JMJs, and thus controlled genome-wide gene expression in plants. We show that nuclear targeting is regulated by environmental signals and that KGDH is enriched at thousands of loci in . Chromatin-bound KGDH catalyzes α-KG decarboxylation and thus may limit its local availability to KGDH-coupled JMJs, inhibiting histone demethylation. Thus, our results uncover a regulatory mechanism for histone demethylations by JMJs.
Topics: Arabidopsis; Arabidopsis Proteins; Cell Nucleus; Chromatin; Demethylation; Histone Demethylases; Histones; Jumonji Domain-Containing Histone Demethylases; Ketoglutarate Dehydrogenase Complex; Gene Expression Regulation, Plant
PubMed: 37440635
DOI: 10.1126/science.adf8822 -
Cell Stem Cell Aug 2023TET2 is recurrently mutated in acute myeloid leukemia (AML) and its deficiency promotes leukemogenesis (driven by aggressive oncogenic mutations) and enhances leukemia...
TET2 is recurrently mutated in acute myeloid leukemia (AML) and its deficiency promotes leukemogenesis (driven by aggressive oncogenic mutations) and enhances leukemia stem cell (LSC) self-renewal. However, the underlying cellular/molecular mechanisms have yet to be fully understood. Here, we show that Tet2 deficiency significantly facilitates leukemogenesis in various AML models (mediated by aggressive or less aggressive mutations) through promoting homing of LSCs into bone marrow (BM) niche to increase their self-renewal/proliferation. TET2 deficiency in AML blast cells increases expression of Tetraspanin 13 (TSPAN13) and thereby activates the CXCR4/CXCL12 signaling, leading to increased homing/migration of LSCs into BM niche. Mechanistically, TET2 deficiency results in the accumulation of methyl-5-cytosine (mC) modification in TSPAN13 mRNA; YBX1 specifically recognizes the mC modification and increases the stability and expression of TSPAN13 transcripts. Collectively, our studies reveal the functional importance of TET2 in leukemogenesis, leukemic blast cell migration/homing, and LSC self-renewal as an mRNA mC demethylase.
Topics: Humans; RNA, Messenger; Leukemia, Myeloid, Acute; Bone Marrow; Carcinogenesis; Stem Cells; Demethylation; Neoplastic Stem Cells; Tetraspanins; DNA-Binding Proteins; Dioxygenases
PubMed: 37541212
DOI: 10.1016/j.stem.2023.07.001 -
Cancer Cell Jun 2023Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA and activates type I interferon signaling and plays an essential role in antitumor immunity....
Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA and activates type I interferon signaling and plays an essential role in antitumor immunity. However, it remains unclear whether the cGAS-mediated antitumor activity is affected by nutrient status. Here, our study reports that methionine deprivation enhances cGAS activity by blocking its methylation, which is catalyzed by methyltransferase SUV39H1. We further show that methylation enhances the chromatin sequestration of cGAS in a UHRF1-dependent manner. Blocking cGAS methylation enhances cGAS-mediated antitumor immunity and suppresses colorectal tumorigenesis. Clinically, cGAS methylation in human cancers correlates with poor prognosis. Thus, our results indicate that nutrient stress promotes cGAS activation via reversible methylation, and suggest a potential therapeutic strategy for targeting cGAS methylation in cancer treatment.
Topics: Humans; Chromatin; Methionine; Nucleotidyltransferases; DNA; Immunity, Innate; Demethylation; CCAAT-Enhancer-Binding Proteins; Ubiquitin-Protein Ligases
PubMed: 37267951
DOI: 10.1016/j.ccell.2023.05.005 -
Science (New York, N.Y.) Dec 2022Neurons harbor high levels of single-strand DNA breaks (SSBs) that are targeted to neuronal enhancers, but the source of this endogenous damage remains unclear. Using...
Neurons harbor high levels of single-strand DNA breaks (SSBs) that are targeted to neuronal enhancers, but the source of this endogenous damage remains unclear. Using two systems of postmitotic lineage specification-induced pluripotent stem cell-derived neurons and transdifferentiated macrophages-we show that thymidine DNA glycosylase (TDG)-driven excision of methylcytosines oxidized with ten-eleven translocation enzymes (TET) is a source of SSBs. Although macrophage differentiation favors short-patch base excision repair to fill in single-nucleotide gaps, neurons also frequently use the long-patch subpathway. Disrupting this gap-filling process using anti-neoplastic cytosine analogs triggers a DNA damage response and neuronal cell death, which is dependent on TDG. Thus, TET-mediated active DNA demethylation promotes endogenous DNA damage, a process that normally safeguards cell identity but can also provoke neurotoxicity after anticancer treatments.
Topics: Cell Differentiation; DNA Demethylation; Induced Pluripotent Stem Cells; Neurons; DNA Breaks, Single-Stranded; Enhancer Elements, Genetic; Thymine DNA Glycosylase; DNA Repair; 5-Methylcytosine; Humans; Cell Transdifferentiation
PubMed: 36454826
DOI: 10.1126/science.add9838 -
Nature Biotechnology Dec 2021RNA N-methyladenosine (mA) modifications are essential in plants. Here, we show that transgenic expression of the human RNA demethylase FTO in rice caused a more than...
RNA N-methyladenosine (mA) modifications are essential in plants. Here, we show that transgenic expression of the human RNA demethylase FTO in rice caused a more than threefold increase in grain yield under greenhouse conditions. In field trials, transgenic expression of FTO in rice and potato caused ~50% increases in yield and biomass. We demonstrate that the presence of FTO stimulates root meristem cell proliferation and tiller bud formation and promotes photosynthetic efficiency and drought tolerance but has no effect on mature cell size, shoot meristem cell proliferation, root diameter, plant height or ploidy. FTO mediates substantial mA demethylation (around 7% of demethylation in poly(A) RNA and around 35% decrease of mA in non-ribosomal nuclear RNA) in plant RNA, inducing chromatin openness and transcriptional activation. Therefore, modulation of plant RNA mA methylation is a promising strategy to dramatically improve plant growth and crop yield.
Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Biomass; Demethylation; Humans; Oryza; Plants, Genetically Modified; RNA, Plant; Solanum tuberosum
PubMed: 34294912
DOI: 10.1038/s41587-021-00982-9 -
Experimental & Molecular Medicine Aug 2023Improving health and delaying aging is the focus of medical research. Previous studies have shown that mesenchymal stem cell (MSC) senescence is closely related to...
Improving health and delaying aging is the focus of medical research. Previous studies have shown that mesenchymal stem cell (MSC) senescence is closely related to organic aging and the development of aging-related diseases such as osteoarthritis (OA). m6A is a common RNA modification that plays an important role in regulating cell biological functions, and ALKBH5 is one of the key m6A demethylases. However, the role of m6A and ALKBH5 in MSC senescence is still unclear. Here, we found that the m6A level was enhanced and ALKBH5 expression was decreased in aging MSCs induced by multiple replications, HO stimulation or UV irradiation. Downregulation of ALKBH5 expression facilitated MSC senescence by enhancing the stability of CYP1B1 mRNA and inducing mitochondrial dysfunction. In addition, IGF2BP1 was identified as the m6A reader restraining the degradation of m6A-modified CYP1B1 mRNA. Furthermore, Alkbh5 knockout in MSCs aggravated spontaneous OA in mice, and overexpression of Alkbh5 improved the efficacy of MSCs in OA. Overall, this study revealed a novel mechanism of m6A in MSC senescence and identified promising targets to protect against aging and OA.
Topics: Animals; Mice; Demethylation; Hydrogen Peroxide; Mesenchymal Stem Cells; Osteoarthritis; RNA Stability; RNA, Messenger; AlkB Homolog 5, RNA Demethylase; Cytochrome P-450 CYP1B1
PubMed: 37524872
DOI: 10.1038/s12276-023-01059-0 -
Nature Cell Biology Oct 2023All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes...
All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.
Topics: Mechanistic Target of Rapamycin Complex 1; Leucine; Histones; Signal Transduction; Iron; Regulatory-Associated Protein of mTOR; Demethylation
PubMed: 37749225
DOI: 10.1038/s41556-023-01225-6 -
Cancer Research Nov 2022Resistance to HER2-targeted therapy represents a significant challenge for the successful treatment of patients with breast cancer with HER2-positive tumors. Through a...
UNLABELLED
Resistance to HER2-targeted therapy represents a significant challenge for the successful treatment of patients with breast cancer with HER2-positive tumors. Through a global mass spectrometry-based proteomics approach, we discovered that the expression of the N6-methyladenosine (m6A) demethylase ALKBH5 was significantly upregulated in HER2-targeted therapy-resistant breast cancer cells. Elevated expression of ALKBH5 was sufficient to confer resistance to HER2-targeted therapy, and specific knockdown of ALKBH5 rescued the efficacy of trastuzumab and lapatinib in resistant breast cancer cells. Mechanistically, ALKBH5 promoted m6A demethylation of GLUT4 mRNA and increased GLUT4 mRNA stability in a YTHDF2-dependent manner, resulting in enhanced glycolysis in resistant breast cancer cells. In breast cancer tissues obtained from patients with poor response to HER2-targeted therapy, increased expression of ALKBH5 or GLUT4 was observed and was significantly associated with poor prognosis in the patients. Moreover, suppression of GLUT4 via genetic knockdown or pharmacologic targeting with a specific inhibitor profoundly restored the response of resistant breast cancer cells to trastuzumab and lapatinib, both in vitro and in vivo. In conclusion, ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes resistance to HER2-targeted therapy, and targeting the ALKBH5/GLUT4 axis has therapeutic potential for treating patients with breast cancer refractory to HER2-targeted therapies.
SIGNIFICANCE
GLUT4 upregulation by ALKBH5-mediated m6A demethylation induces glycolysis and resistance to HER2-targeted therapy and represents a potential therapeutic target for treating HER2-positive breast cancer.
Topics: Female; Humans; AlkB Homolog 5, RNA Demethylase; Breast Neoplasms; Demethylation; Glycolysis; Lapatinib; RNA, Messenger; Trastuzumab
PubMed: 36069931
DOI: 10.1158/0008-5472.CAN-22-0800