DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors.

Honeywell, Richard J.; Sarkisjan, Dzjemma; Kristensen, Michael Holmsgaard; Klerk, Daniel J de; Peters, Godefridus J.

doi:10.1080/15257770.2018.1498516

Cited by 19 publications

(20 citation statements)

References 24 publications

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“…DNMT1 expression can be downregulated by RX-3117, which affects DNA methylation. DNMT1 shows a large variation in expression in various cancer cell lines, human xenografts and human tumor tissues [48]. This can easily be measured using either PCR or immunohistochemistry, both in tumor tissue and normal cells such as white blood cells.…”

Section: Dna Methyltransferasesmentioning

confidence: 99%

RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment

Balboni

Hassouni

Honeywell

et al. 2019

Expert Opinion on Investigational Drugs

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Introduction: RX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The agent has excellent activity against various cancer cell lines and xenografts including gemcitabine-resistant variants and it has excellent oral bioavailability; it is not a substrate for the degradation enzyme cytidine deaminase. RX-3117 is being evaluated at a daily oral schedule of 700 mg (5 days/week for 3 weeks) which results in plasma levels in the micromolar range that have been shown to be cytotoxic to cancer cells. It has shown clinical activity in refractory bladder cancer and pancreatic cancer. Areas covered: The review provides an overview of the relevant market and describes the mechanism of action, main pharmacokinetic/pharmacodynamic features and clinical development of this investigational small molecule. Expert opinion: RX-3117 is selectively activated by uridine-cytidine kinase 2 (UCK2), which is expressed only in tumors and has a dual mechanism of action: DNA damage and inhibition of DNA methyltransferase 1 (DNMT1). Because of its tumor selective activation, novel mechanism of action, excellent oral bioavailability and candidate biomarkers for patient selection, RX-3117 has the potential to replace gemcitabine in the treatment of a spectrum of cancer types.

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Section: Dna Methyltransferasesmentioning

confidence: 99%

RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment

Balboni

Hassouni

Honeywell

et al. 2019

Expert Opinion on Investigational Drugs

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“…Other studies reported association of this polymorphism with global methylation levels of leukocyte DNA [31], with MTHFR methylation levels in blood DNA of valproate-treated patients with epilepsy [32], and with hypermethylation of tumor suppressor genes in cancer specimens [33] or adjacent healthy tissues [17]. The present finding of a correlation between the MTR 2756A > G polymorphism and DNMT1 promoter methylation levels in blood DNA not only strengthens the contribution of this genetic variant to the DNA methylation levels in leukocytes, but it could also be of relevance for those disorders, such as hematological malignancies, autoimmune/inflammatory disorders, and solid tumors, that are linked to impaired DNMT1 methylation and/or expression [5][6][7][8][9][10][11][12]. For example, changes in DNMT1 methylation levels were observed in peripheral blood DNA samples from ALL patients [8], the MTR 2756A > G polymorphism was linked to the risk of pediatric ALL [34], and several maternal polymorphisms of the MTR gene were recently proposed as responsible of aberrant methylation of ALL-related genes in their offspring [35].…”

Section: Discussionmentioning

confidence: 64%

“…As discussed above, DNMT1 is the main enzyme responsible for the maintenance of DNA methylation during cell division, and previous studies revealed the existence of a CpG island in the promoter/5' untranslated region (5'UTR) of the DNMT1 gene itself, whose methylation levels regulate DNMT1 gene expression in both healthy and pathological tissues [5][6][7][8][9][10][11][12]. In this regard, increased DNMT1 promoter methylation resulting in decreased gene expression levels was observed in blood DNA of individuals with ankylosing spondylitis, a chronic inflammatory autoimmune disease [5].…”

Section: Introductionmentioning

confidence: 99%

“…Changes in DNMT1 promoter methylation were also observed in peripheral blood DNA samples from patients with acute lymphoblastic leukemia (ALL) and were linked to the DNMT1 expression pattern in the patients [8]. Furthermore, DNMT1 expression levels in white blood cells of healthy individuals showed a large inter-individual variability [9]. Hypermethylation of the Dnmt1 promoter was also responsible for reduced gene expression levels in various tissues of animal models of asthma [10].…”

Section: Introductionmentioning

confidence: 99%

“…Hypermethylation of the Dnmt1 promoter was also responsible for reduced gene expression levels in various tissues of animal models of asthma [10]. The investigation of DNMT1 methylation, expression, and protein levels in solid tumors showed a large variability according to the investigated cell line or to the cancer subtype [9,[11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels

et al. 2019

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DNA methyltransferase 1 (DNMT1) is responsible for the maintenance of DNA methylation patterns during cell division. Several human diseases are characterized by impaired DNMT1 gene methylation, but less is known about the factors that regulate DNMT1 promoter methylation levels. Dietary folates and related B-vitamins are essential micronutrients for DNA methylation processes, and we performed the present study to investigate the contribution of circulating folate, vitamin B12, homocysteine, and common polymorphisms in folate pathway genes to the DNMT1 gene methylation levels. We investigated DNMT1 gene methylation levels in peripheral blood DNA samples from 215 healthy individuals. All the DNA samples were genotyped for MTHFR 677C > T (rs1801133) and 1298A > C (rs1801131), MTRR 66A > G (rs1801394), MTR 2756A > G (rs1805087), SLC19A1 (RFC1) 80G > A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp insertion/deletion (indel) (rs34489327), DNMT3A -448A > G (rs1550117), and DNMT3B -149C > T (rs2424913) polymorphisms. Circulating homocysteine, folate, and vitamin B12 levels were available from 158 of the recruited individuals. We observed an inverse correlation between plasma homocysteine and DNMT1 methylation levels. Furthermore, both MTR rs1805087 and TYMS rs34743033 polymorphisms showed a statistically significant effect on DNMT1 methylation levels. The present study revealed several correlations between the folate metabolic pathway and DNMT1 promoter methylation that could be of relevance for those disorders characterized by altered DNA methylation.

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DNMT1 maintains the methylation of miR‐152‐3p to regulate TMSB10 expression, thereby affecting the biological characteristics of colorectal cancer cells

Wang

Zhang

et al. 2020

IUBMB Life

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Objective: DNA methyltransferases (DNMTs) take on a relevant role in epigenetic control of cancer proliferation and cell survival. However, the molecular mechanisms underlying the establishment and maintenance of DNA methylation in human cancer remain to be fully elucidated. This study was to investigate that how DNMT1 affected the biological characteristics of colorectal cancer (CRC) cells via modulating methylation of microRNA (miR)-152-3p and thymosin β 10 (TMSB10) expression. Methods: DNMT1, miR-152-3p, and TMSB10 expression, and the methylation of miR-152-3p in CRC tissues and cells were detected. SW-480 and HCT-116 CRC cells were transfected with DNMT1 or miR-152-3p-related sequences or plasmids to explore their characters in biological functions of CRC cells. The binding relationship between DNMT1 and miR-152-3p and the targeting relationship between miR-152-3p and TMSB10 were analyzed. The tumor growth was also detected in vivo. Results: Upregulated DNMT1, TMSB10, reduced miR-152-3p, and methylated miR-152-3p were detected in CRC tissues and cells. Silenced DNMT1 or upregulated miR-152-3p reduced TMSB10 expression and suppressed CRC progression and tumor growth. Moreover, elevated DNMT1 could reverse the effect of miR-152-3p upregulation on CRC development and tumor growth. DNMT1 maintained methylation of miR-152-3p. TMSB10 was the direct target gene of miR-152-3p. Conclusion: The study highlights that silenced DNMT1 results in nonmethylated miR-152-3p to depress TMSB10 expression, thereby inhibiting CRC development, which provides a new approach for CRC therapy.

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DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors.

Abstract: View related articles View Crossmark data Citing articles: 8 View citing articles DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors.

Cited by 19 publications

References 24 publications

RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment

RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment

Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels

DNMT1 maintains the methylation of miR‐152‐3p to regulate TMSB10 expression, thereby affecting the biological characteristics of colorectal cancer cells

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