Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aberrant methylation of the CpG island promoter regions acquired by tumor cells is one mechanism for loss of gene function. The high methylation rate for RB1 and death-associated protein-kinase gene (DAP-kinase) (60 and 90%, respectively) previously found in brain metastases suggests this mechanism could be non-randomly associated to tumor progression and metastasis. Thus, in addition to these two genes, we determined the methylation status of the genes p16INK4a, glutathione S-transferase P1 (GSTP1), O6-methylguanine DNA methyltransferase (MGMT), thrombospondin-1 (THBS1), p14ARF, TP53, p73, and tissue inhibitor of metalloproteinase 3 (TIMP-3), in 18 brain metastases of solid tumors, with methylation specific PCR. The metastases were derived from malignant melanoma (three cases), lung carcinoma (six cases), breast carcinoma (three cases), ovarian carcinoma (two cases) and one each from colon, kidney, bladder and undifferentiated carcinoma. We detected methylation levels in the tumor samples of 83% in p16INK4a, 72% in DAP-kinase, 56% in THBS1, 50% in RB1, 39% in MGMT, 33% in GSTP1 and p14ARF each, 22% in p73 and TIMP-3 each, and 11% in TP53. The methylation index (number of genes methylated/number of genes tested) varied between 0.1 and 0.6, with an average of 0.42, indicating that a high grade of gene methylation accumulates parallel to the tumor metastasis process. Our data suggest an important role for gene methylation in the development of brain metastases, primarily involving epigenetic silencing of DAP-kinase, THBS1 and the cell-cycle regulators RB1/p16INK4a.
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PMID:Promoter methylation status of multiple genes in brain metastases of solid tumors. 1465 77

Aberrant DNA methylation and increased expression of DNA methyltransferases (DNMTs) are features of tumor cells. To investigate roles for DNMTs during hepatocarcinogenesis, we examined DNMT expression at both the mRNA and protein level in hepatocellular carcinomas (HCCs) and paired non-neoplastic liver tissues, along with measuring the DNA methylation status of five tumor suppressor genes. Expression of DNMT1, DNMT3a and DNMT3b mRNA was detected in 33.3, 59.3, and 55.6% of HCCs and 40.7, 22.2, and 0% of non-neoplastic liver tissues, respectively. DNMT1 and DNMT3a were immunoreactive in 100 and 48% of HCCs and 52 and 0% of non-neoplastic liver tissues. The DNMT3a mRNA expression profile showed significant correlation with its immunoreactivity (P=0.022). DNA methylation status of five tumor suppressor genes, HIC-1, p16, RASSF1A, p53, and RB1 was detected in 85.2, 48.1, 44.4, 22.2, and 0% of HCCs, respectively. There was no significant correlation between DNMT mRNA expression and DNA methylation (P>0.05). DNMT immunoreactivity was also not associated with DNA methylation except HIC-1 (P=0.036) and p53 methylation (P=0.009). Despite the lack of correlation between DNA methylation status and DNMT expression, the frequency of hypermethylation of tumor suppressor genes remained relatively high in HCCs, suggesting that regional DNA hypermethylation is involved in hepatocarcinogenesis and that there may be other mechanisms for increasing DNA methylation.
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PMID:DNA methyltransferase expression and DNA hypermethylation in human hepatocellular carcinoma. 1588 82

Melanoma is among the most aggressive and treatment-resistant human cancers. Aberrant histone H3 methylation at Lys 9 (H3K9) correlates with carcinogenic gene silencing, but the significance of suppressor of variegation 3-9 homolog 1 (SUV39H1), an H3K9-specific methyltransferase, in melanoma initiation and progression remains unclear. Here, we show that SUV39H1-mediated H3K9 trimethylation facilitates retinoblastoma ( RB) 1 promoter CpG island methylation by interacting with DNA methyltransferase 3A and decreasing RB mRNA and protein in melanoma cells. Reduced RB abundance, in turn, impairs E2F1 transcriptional inhibition, leading to increased peptidyl-prolyl cis-trans isomerase never-in-mitosis A (NIMA)-interacting 1 (PIN1) levels, human keratinocyte neoplastic cell transformation, and melanoma tumorigenesis via enhanced rapidly accelerated fibrosarcoma 1(RAF1)-MEK-ERK signaling pathway activation. In a synergistic model with B16-F1 murine melanoma cells, SUV39H1 and PIN1 overexpression increased melanoma growth, which was abrogated by their inhibition in SUV39H1-overexpressing B16-F1 mice. SUV39H1 also positively correlated with PIN1 expression in human melanoma. Our studies establish SUV39H1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.-Kim, G., Kim, J.-Y., Lim, S.-C., Lee, K. Y., Kim, O., Choi, H. S. SUV39H1/DNMT3A-dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development.
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PMID:SUV39H1/DNMT3A-dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development. 2975 May 76

Moraxella catarrhalis is a human-adapted pathogen, and a major cause of otitis media (OM) and exacerbations of chronic obstructive pulmonary disease. The species is comprised of two main phylogenetic lineages, RB1 and RB2/3. Restriction-modification (R-M) systems are among the few lineage-associated genes identified in other bacterial genera and have multiple functions including defense against foreign invading DNA, maintenance of speciation, and epigenetic regulation of gene expression. Here, we define the repertoire of R-M systems in 51 publicly available M. catarrhalis genomes and report their distribution among M. catarrhalis phylogenetic lineages. An association with phylogenetic lineage (RB1 or RB2/3) was observed for six R-M systems, which may contribute to the evolution of the lineages by restricting DNA transformation. In addition, we observed a relationship between a mutually exclusive Type I R-M system and a Type III R-M system at a single locus conserved throughout a geographically and clinically diverse set of M. catarrhalis isolates. The Type III R-M system at this locus contains the phase-variable Type III DNA methyltransferase, modM, which controls a phasevarion (phase-variable regulon). We observed an association between modM presence and OM-associated middle ear isolates, indicating a potential role for ModM-mediated epigenetic regulation in OM pathobiology.
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PMID:Moraxella catarrhalis Restriction-Modification Systems Are Associated with Phylogenetic Lineage and Disease. 3033 44

Macroautophagy/autophagy is a conserved catabolic pathway that targets cytoplasmic components for their degradation and recycling in an autophagosome-dependent lysosomal manner. Under physiological conditions, this process maintains cellular homeostasis. However, autophagy can be stimulated upon different forms of cellular stress, ranging from nutrient starvation to exposure to drugs. Thus, this pathway can be seen as a central component of the integrated and adaptive stress response. Here, we report that even brief induction of autophagy is coupled in vitro to a persistent downregulation of the expression of MAP1LC3 isoforms, which are key components of the autophagy core machinery. In fact, DNA-methylation mediated by de novo DNA methyltransferase DNMT3A of MAP1LC3 loci upon autophagy stimulation leads to the observed long-term decrease of MAP1LC3 isoforms at transcriptional level. Finally, we report that the downregulation of MAP1LC3 expression can be observed in vivo in zebrafish larvae and mice exposed to a transient autophagy stimulus. This epigenetic memory of autophagy provides some understanding of the long-term effect of autophagy induction and offers a possible mechanism for its decline upon aging, pathological conditions, or in response to treatment interventions. Abbreviations: ACTB: actin beta; ATG: autophagy-related; 5-Aza: 5-aza-2'-deoxycytidine; BafA1: bafilomycin A1; CBZ: carbamazepine; CDKN2A: cyclin dependent kinase inhibitor 2A; ChIP: chromatin immunoprecipitation; Clon.: clonidine; CpG: cytosine-guanine dinucleotide: DMSO: dimethyl sulfoxide; DNA: deoxyribonucleic acid; DNMT: DNA methyltransferase; DNMT1: DNA methyltransferase 1; DNMT3A: DNA methyltransferase alpha; DNMT3B: DNA methyltransferase beta; dpf: days post-fertilization; EBSS: Earle's balanced salt solution; EM: Zebrafish embryo medium; GABARAP: GABA type A receptor associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GRO-Seq: Global Run-On sequencing; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3A: microtubule-associated protein 1 light chain 3 alpha; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MAP1LC3B2: microtubule-associated protein 1 light chain 3 beta 2; MEM: minimum essential medium; MEF: mouse embryonic fibroblasts; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; PBS: phosphate-buffered saline; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RT-qPCR: quantitative reverse transcription polymerase chain reaction; SQSTM1/p62: sequestosome 1; Starv.: starvation; Treh.: trehalose; ULK1: unc-51 like autophagy activating kinase 1.
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PMID:The DNA methyltransferase DNMT3A contributes to autophagy long-term memory. 3287 28

Although molecular targeted therapies have recently displayed therapeutic effects in acute myeloid leukemia (AML), limited response and acquired resistance remain common problems. Numerous studies have associated autophagy, an essential degradation process involved in the cellular response to stress, with the development and therapeutic response of cancers including AML. Thus, we review studies on the role of autophagy in AML development and summarize the linkage between autophagy and several recurrent genetic abnormalities in AML, highlighting the potential of capitalizing on autophagy modulation in targeted therapy for AML. Abbreviations: AML: acute myeloid leukemia; AMPK: AMP-activated protein kinase; APL: acute promyelocytic leukemia; ATG: autophagy related; ATM: ATM serine/threonine kinase; ATO: arsenic trioxide; ATRA: all trans retinoic acid; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BET proteins, bromodomain and extra-terminal domain family; CMA: chaperone-mediated autophagy; CQ: chloroquine; DNMT, DNA methyltransferase; DOT1L: DOT1 like histone lysine methyltransferase; FLT3: fms related receptor tyrosine kinase 3; FIS1: fission, mitochondrial 1; HCQ: hydroxychloroquine; HSC: hematopoietic stem cell; IDH: isocitrate dehydrogenase; ITD: internal tandem duplication; KMT2A/MLL: lysine methyltransferase 2A; LSC: leukemia stem cell; MDS: myelodysplastic syndromes; MTORC1: mechanistic target of rapamycin kinase complex 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NPM1: nucleophosmin 1; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PML: PML nuclear body scaffold; ROS: reactive oxygen species; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SAHA: vorinostat; SQSTM1: sequestosome 1; TET2: tet methylcytosine dioxygenase 2; TKD: tyrosine kinase domain; TKI: tyrosine kinase inhibitor; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VPA: valproic acid; WDFY3/ALFY: WD repeat and FYVE domain containing 3.
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PMID:The role of autophagy in targeted therapy for acute myeloid leukemia. 3291 24