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

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

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

DNA methylation plays an important role in carcinogenesis and aberrant methylation patterns have been found in many tumors. Methylation is regulated by DNA methyltransferases (DNMT), catalyzing DNA methylation. Therefore inhibition of DNMT is an interesting target for anticancer treatment. RX-3117 (fluorocyclopentenylcytosine) is a novel demethylating antimetabolite that is currently being studied in clinical trials in metastatic bladder and pancreatic cancers. The active nucleotide of RX-3117 is incorporated into DNA leading to downregulation of DNMT1, the maintenance DNA methylation enzyme. Since DNMT1 is a major target for the activity of RX-3117, DNMT1 may be a potential predictive biomarker. Therefore, DNMT1 protein and mRNA expression was investigated in 19 cancer cell lines, 26 human xenografts (hematological, lung, pancreatic, colon, bladder cancer) and 10 colorectal cancer patients. The DNMT1 mRNA expression showed large variation between cell lines (100-fold) and the 26 xenografts (1100-fold) investigated. The DNMT1 protein was overexpressed in colon tumours from patients compared to non-malignant mucosa from the same patients (P = 0.02). The DNA methylation in these patients was significantly higher in tumour tissues compared to normal mucosa (P = 0.001). DNMT1 expression in normal white blood cells also showed a large variation. In conclusion, the large variation in DNMT1 expression may serve as a potential biomarker for demethylating therapy such as with RX-3117.
Original languageEnglish
Pages (from-to)1-13
JournalNucleosides, Nucleotides and Nucleic Acids
DOIs
Publication statusE-pub ahead of print - 19 Jan 2019

Cite this

@article{fa70881e22a047d9aa595d3f21cb453a,
title = "DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors.",
abstract = "DNA methylation plays an important role in carcinogenesis and aberrant methylation patterns have been found in many tumors. Methylation is regulated by DNA methyltransferases (DNMT), catalyzing DNA methylation. Therefore inhibition of DNMT is an interesting target for anticancer treatment. RX-3117 (fluorocyclopentenylcytosine) is a novel demethylating antimetabolite that is currently being studied in clinical trials in metastatic bladder and pancreatic cancers. The active nucleotide of RX-3117 is incorporated into DNA leading to downregulation of DNMT1, the maintenance DNA methylation enzyme. Since DNMT1 is a major target for the activity of RX-3117, DNMT1 may be a potential predictive biomarker. Therefore, DNMT1 protein and mRNA expression was investigated in 19 cancer cell lines, 26 human xenografts (hematological, lung, pancreatic, colon, bladder cancer) and 10 colorectal cancer patients. The DNMT1 mRNA expression showed large variation between cell lines (100-fold) and the 26 xenografts (1100-fold) investigated. The DNMT1 protein was overexpressed in colon tumours from patients compared to non-malignant mucosa from the same patients (P = 0.02). The DNA methylation in these patients was significantly higher in tumour tissues compared to normal mucosa (P = 0.001). DNMT1 expression in normal white blood cells also showed a large variation. In conclusion, the large variation in DNMT1 expression may serve as a potential biomarker for demethylating therapy such as with RX-3117.",
author = "Honeywell, {Richard J.} and Dzjemma Sarkisjan and Kristensen, {Michael H.} and {de Klerk}, {Daniel J.} and Peters, {Godefridus J.}",
year = "2019",
month = "1",
day = "19",
doi = "10.1080/15257770.2018.1498516",
language = "English",
pages = "1--13",
journal = "Nucleosides, Nucleotides and Nucleic Acids",
issn = "1525-7770",
publisher = "Taylor and Francis Ltd.",

}

DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors. / Honeywell, Richard J.; Sarkisjan, Dzjemma; Kristensen, Michael H.; de Klerk, Daniel J.; Peters, Godefridus J.

In: Nucleosides, Nucleotides and Nucleic Acids, 19.01.2019, p. 1-13.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors.

AU - Honeywell, Richard J.

AU - Sarkisjan, Dzjemma

AU - Kristensen, Michael H.

AU - de Klerk, Daniel J.

AU - Peters, Godefridus J.

PY - 2019/1/19

Y1 - 2019/1/19

N2 - DNA methylation plays an important role in carcinogenesis and aberrant methylation patterns have been found in many tumors. Methylation is regulated by DNA methyltransferases (DNMT), catalyzing DNA methylation. Therefore inhibition of DNMT is an interesting target for anticancer treatment. RX-3117 (fluorocyclopentenylcytosine) is a novel demethylating antimetabolite that is currently being studied in clinical trials in metastatic bladder and pancreatic cancers. The active nucleotide of RX-3117 is incorporated into DNA leading to downregulation of DNMT1, the maintenance DNA methylation enzyme. Since DNMT1 is a major target for the activity of RX-3117, DNMT1 may be a potential predictive biomarker. Therefore, DNMT1 protein and mRNA expression was investigated in 19 cancer cell lines, 26 human xenografts (hematological, lung, pancreatic, colon, bladder cancer) and 10 colorectal cancer patients. The DNMT1 mRNA expression showed large variation between cell lines (100-fold) and the 26 xenografts (1100-fold) investigated. The DNMT1 protein was overexpressed in colon tumours from patients compared to non-malignant mucosa from the same patients (P = 0.02). The DNA methylation in these patients was significantly higher in tumour tissues compared to normal mucosa (P = 0.001). DNMT1 expression in normal white blood cells also showed a large variation. In conclusion, the large variation in DNMT1 expression may serve as a potential biomarker for demethylating therapy such as with RX-3117.

AB - DNA methylation plays an important role in carcinogenesis and aberrant methylation patterns have been found in many tumors. Methylation is regulated by DNA methyltransferases (DNMT), catalyzing DNA methylation. Therefore inhibition of DNMT is an interesting target for anticancer treatment. RX-3117 (fluorocyclopentenylcytosine) is a novel demethylating antimetabolite that is currently being studied in clinical trials in metastatic bladder and pancreatic cancers. The active nucleotide of RX-3117 is incorporated into DNA leading to downregulation of DNMT1, the maintenance DNA methylation enzyme. Since DNMT1 is a major target for the activity of RX-3117, DNMT1 may be a potential predictive biomarker. Therefore, DNMT1 protein and mRNA expression was investigated in 19 cancer cell lines, 26 human xenografts (hematological, lung, pancreatic, colon, bladder cancer) and 10 colorectal cancer patients. The DNMT1 mRNA expression showed large variation between cell lines (100-fold) and the 26 xenografts (1100-fold) investigated. The DNMT1 protein was overexpressed in colon tumours from patients compared to non-malignant mucosa from the same patients (P = 0.02). The DNA methylation in these patients was significantly higher in tumour tissues compared to normal mucosa (P = 0.001). DNMT1 expression in normal white blood cells also showed a large variation. In conclusion, the large variation in DNMT1 expression may serve as a potential biomarker for demethylating therapy such as with RX-3117.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85060342637&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/30663502

U2 - 10.1080/15257770.2018.1498516

DO - 10.1080/15257770.2018.1498516

M3 - Article

SP - 1

EP - 13

JO - Nucleosides, Nucleotides and Nucleic Acids

JF - Nucleosides, Nucleotides and Nucleic Acids

SN - 1525-7770

ER -