MicroRNA-140 acts as a liver tumor suppressor by controlling NF-κB activity by directly targeting DNA methyltransferase 1 (Dnmt1) expression

Prenatal nutritional constraint induces an altered metabolic phenotype in the offspring which in humans confers an increased risk of non-communicable disease. Feeding a protein-restricted (PR) diet to pregnant rats causes hypomethylation of specific gene promoters in the offspring and alters the phenotype. We investigated how altered epigenetic regulation of the hepatic glucocorticoid receptor (GR) 110 promoter is induced in the offspring. Rats were fed a control (180 g casein/kg) or a PR (90 g casein/kg) diet throughout pregnancy, and chow during lactation. Offspring were killed at postnatal day 34 (n 5 per maternal dietary group). Methylation-sensitive PCR showed that GR110 promoter methylation was 33 % lower (P < 0·001) and GR expression 84 % higher (P < 0·05) in the PR offspring. Reverse transcription–PCR showed that DNA methyltransferase-1 (Dnmt1) expression was 17 % lower (P < 0·05) in PR offspring, while Dnmt3a/b and methyl binding domain protein-2 expression was not altered. Thus hypomethylation of the GR110 promoter may result from lower capacity to methylate hemimethylated DNA during mitosis. Histone modifications which facilitate transcription were increased at the GR110 promoter (147–921 %, P < 0·001), while those that suppress methylation were decreased (54 %, P < 0·01) or similar to controls. In human umbilical cord (n 15), there was a 2-fold difference between the highest and lowest level of GR1-CTotal promoter methylation. Dnmt1, but not Dnmt3a, expression predicted 49 % (P = 0·003) of the variation in GR1-CTotal promoter methylation. These findings suggest that induction in the offspring of altered epigenetic regulation of the hepatic GR110 promoter, and hence metabolic phenotype, may be due to reduced Dnmt1 expression.

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Knockdown of DNA methyltransferase-1 inhibits proliferation and derepresses tumor suppressor genes in myeloma cells

Oncology Letters ◽

10.3892/ol.2014.2481 ◽

2014 ◽

Vol 8 (5) ◽

pp. 2130-2134 ◽

Cited By ~ 8

Author(s):

WENWEN ZHOU ◽

HUYING CHEN ◽

XIULI HONG ◽

XIAOQING NIU ◽

QUANYI LU

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Dna Methyltransferase ◽

Dna Methyltransferase 1 ◽

Suppressor Genes ◽

Myeloma Cells ◽

Methyltransferase 1

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RX-3117 (Fluorocyclopentenyl-Cytosine)-Mediated Down-Regulation of DNA Methyltransferase 1 Leads to Protein Expression of Tumor-Suppressor Genes and Increased Functionality of the Proton-Coupled Folate Carrier

International Journal of Molecular Sciences ◽

10.3390/ijms21082717 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2717 ◽

Cited By ~ 1

Author(s):

Dzjemma Sarkisjan ◽

Joris R. Julsing ◽

Btissame El Hassouni ◽

Richard J. Honeywell ◽

Ietje Kathmann ◽

...

Keyword(s):

Tumor Suppressor ◽

Protein Expression ◽

Tumor Suppressor Genes ◽

Dna Methyltransferase ◽

Functional Assay ◽

Dna Methyltransferase 1 ◽

Suppressor Genes ◽

Resistant Variant ◽

E Cadherin ◽

Methyltransferase 1

(1) Background: RX-3117 (fluorocyclopentenyl-cytosine) is a cytidine analog that inhibits DNA methyltransferase 1 (DNMT1). We investigated the mechanism and potential of RX-3117 as a demethylating agent in several in vitro models. (2) Methods: we used western blotting to measure expression of several proteins known to be down-regulated by DNA methylation: O6-methylguanine-DNA methyltransferase (MGMT) and the tumor-suppressor genes, p16 and E-cadherin. Transport of methotrexate (MTX) mediated by the proton-coupled folate transporter (PCFT) was used as a functional assay. (3) Results: RX-3117 treatment decreased total DNA-cytosine-methylation in A549 non-small cell lung cancer (NSCLC) cells, and induced protein expression of MGMT, p16 and E-cadherin in A549 and SW1573 NSCLC cells. Leukemic CCRF-CEM cells and the MTX-resistant variant (CEM/MTX, with a deficient reduced folate carrier) have a very low expression of PCFT due to promoter hypermethylation. In CEM/MTX cells, pre-treatment with RX-3117 increased PCFT-mediated MTX uptake 8-fold, and in CEM cells 4-fold. With the reference hypomethylating agent 5-aza-2′-deoxycytidine similar values were obtained. RX-3117 also increased PCFT gene expression and PCFT protein. (4) Conclusion: RX-3117 down-regulates DNMT1, leading to hypomethylation of DNA. From the increased protein expression of tumor-suppressor genes and functional activation of PCFT, we concluded that RX-3117 might have induced hypomethylation of the promotor.

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STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0501959102 ◽

2005 ◽

Vol 102 (19) ◽

pp. 6948-6953 ◽

Cited By ~ 169

Author(s):

Q. Zhang ◽

H. Y. Wang ◽

M. Marzec ◽

P. N. Raghunath ◽

T. Nagasawa ◽

...

Keyword(s):

T Lymphocytes ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Dna Methyltransferase ◽

Tyrosine Phosphatase ◽

Suppressor Gene ◽

Epigenetic Silencing ◽

Dna Methyltransferase 1 ◽

Methyltransferase 1

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miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1

Cell Death and Disease ◽

10.1038/cddis.2017.75 ◽

2017 ◽

Vol 8 (3) ◽

pp. e2663-e2663 ◽

Cited By ~ 20

Author(s):

Hong-fu Xie ◽

Ying-zi Liu ◽

Rui Du ◽

Ben Wang ◽

Meng-ting Chen ◽

...

Keyword(s):

Dna Methylation ◽

Human Skin ◽

Dna Methyltransferase ◽

Skin Aging ◽

Skin Fibroblasts ◽

Luciferase Reporter ◽

Dna Methyltransferase 1 ◽

Human Skin Fibroblasts ◽

Dnmt1 Expression ◽

Methyltransferase 1

Abstract Skin aging is a complicated physiological process and epigenetic feature, including microRNA-mediated regulation and DNA methylation, have been shown to contribute to this process. DNA methylation is regulated by DNA methyltransferase, of which DNA methyltransferase 1 (DNMT1) is the most abundantly known. But evidence supporting its role in skin aging remains scarce, and no report regards its specifical upstream-regulating molecules in the process of skin aging so far. Here, we found that DNMT1 expression was markedly higher in young human skin fibroblasts (HSFs) than that in passage-aged HSFs, and DNMT1 knockdown significantly induced the senescence phenotype in young HSFs. We predicted the upstream miRNAs which could regulate DNMT1 with miRNA databases and found miR-377 had high homology with a sequence in the 3′-UTR of human DNMT1 mRNA. We confirmed that miR-377 was a potential regulator of DNMT1 by luciferase reporter assays. miR-377 expression in passage-aged HSFs was markedly higher than that in the young HSFs. miR-377 overexpression promoted senescence in young HSFs, and inhibition of miR-377 reduced senescence in passage-aged HSFs. Moreover, these functions were mediated by targeting DNMT1. Microfluidic PCR and next-generation bisulfite sequencing of 24 senescent-associated genes’ promoters revealed alterations of the promoter methylation levels of FoxD3, p53, and UTF1 in HSFs treated with miR-377 mimics or inhibitors. We also verified that the miR-377-mediated changes in p53 expression could be reversed by regulation of DNMT1 in HSFs. Similarly, there was a negative correlation between miR-377 and DNMT1 expression in young and photoaged HSFs, HSFs, or skin tissues from UV-unexposed areas of different aged donors. Our results highlight a novel role for miR-377-DNMT1-p53 axis in HSF senescence. These findings shed new light on the mechanisms of skin aging and identify future opportunities for its therapeutic prevention.

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