Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several observations implicate a role for altered DNA methylation in cancer pathogenesis. The global level of DNA methylation is generally lower; however, DNA methyltransferase (Dnmt1) activity is usually higher in tumor cells than in normal cells. The purpose of this study was to investigate whether the Dnmt1 inhibitor, 5-aza-2'-deoxycytidine (aza-dC) would alter the effect of dietary selenium on the formation of aberrant crypts. Weanling rats (n = 60) were fed three concentrations of selenium (deficient, 0.1 and 2.0 mg/kg diet) in a Torula yeast-based diet. Half of the rats were injected weekly with aza-dC (1 mg/kg, subcutaneously) and half were injected with the vehicle control (PBS). After 3.5 wk of consuming the experimental diets, the rats were given two injections of dimethylhydrazine (DMH; 25 mg/kg, intraperitoneally). Rats fed the selenium-deficient diet and injected with PBS had significantly (P < 0.006) more aberrant crypts than rats fed 0.1 or 2.0 mg selenium/kg diet (244 +/- 21 vs. 165 +/- 9 and 132 +/- 14, respectively). In contrast, when rats were injected with aza-dC, there was a significant (P < 0.0001) reduction in aberrant crypt formation and dietary selenium had no effect (62 +/- 8 vs. 77 +/- 13 vs. 54 +/- 8, in rats fed 0, 0.1 and 2.0 mg selenium/kg diet, respectively). HT-29 cells cultured in the absence of selenium had significantly hypomethylated DNA but significantly more Dnmt1 protein expression than cells cultured in the presence of 1 or 2 micromol/L selenium. These results suggest that aza-dC treatment may protect selenium-deficient rats against carcinogen-induced aberrant crypt formation.
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PMID:Dietary selenite and azadeoxycytidine treatments affect dimethylhydrazine-induced aberrant crypt formation in rat colon and DNA methylation in HT-29 cells. 1182 93

Chronic inflammation is strongly associated with an increased risk of developing colorectal cancer. DNA hypermethylation of CpG islands alters the expression of genes in cancer cells and plays an important role in carcinogenesis. Chronic inflammation is also associated with DNA methylation alterations and in a mouse model of inflammation-induced colon tumorigenesis, we previously demonstrated that inflammation-induced tumours have 203 unique regions with DNA hypermethylation compared to uninflamed epithelium. To determine if altering inflammation-induced DNA hypermethylation reduces tumorigenesis, we used the same mouse model and treated mice with the DNA methyltransferase (DNMT) inhibitor decitabine (DAC) throughout the tumorigenesis time frame. DAC treatment caused a significant reduction in colon tumorigenesis. The tumours that did form after DAC treatment had reduced inflammation-specific DNA hypermethylation and alteration of expression of associated candidate genes. When compared, inflammation-induced tumours from control (PBS-treated) mice were enriched for cell proliferation associated gene expression pathways whereas inflammation-induced tumours from DAC-treated mice were enriched for interferon gene signatures. To further understand the altered tumorigenesis, we derived tumoroids from the different tumour types. Interestingly, tumoroids derived from inflammation-induced tumours from control mice maintained many of the inflammation-induced DNA hypermethylation alterations and had higher levels of DNA hypermethylation at these regions than tumoroids from DAC-treated mice. Importantly, tumoroids derived from inflammation-induced tumours from the DAC-treated mice proliferated more slowly than those derived from the inflammation-induced tumours from control mice. These studies suggest that inhibition of inflammation-induced DNA hypermethylation may be an effective strategy to reduce inflammation-induced tumorigenesis.
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PMID:DNA methyltransferase inhibition reduces inflammation-induced colon tumorigenesis. 3124 Sep 97

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