Pancreatic cancer DNMT1 expression and sensitivity to DNMT1 inhibitors

Ang Li, Noriyuki Omura, Seung Mo Hong, Michael S Goggins

Research output: Contribution to journalArticle

Abstract

DNA methyltransferase I (DNMT1) is the major methyltransferase responsible for methylating DNA and is overexpressed in many cancers. DNMT1 is also a therapeutic target for chemotherapy and chemoprevention. We hypothesized that loss of DNMT1 copy number could result in reduced DNMT1 levels and greater sensitivity to DNMT1 inhibitors. We examined DNMT1 expression in pancreatic cancers by immunohistochemistry and western blotting. We also examined DNMT1 copy number in 20 pancreatic cancer cell lines using affymetrix SNP arrays and correlated copy number with DNMT1 expression. We tested eight pancreatic cancer cell lines with DNMT1 inhibitors and measured growth inhibition. We identified overexpression of DNMT1 relative to normal pancreatic duct in 78.7% of pancreatic cancers (37/47) by immunohistochemistry and in 16/20 pancreatic cancer cell lines by western blot. Pancreatic cancer cell lines with loss of DNMT1 alleles tended to have lower DNMT1 expression (three of nine cell lines) compared to those without DNMT1 copy number loss (one of eleven). 5-aza-deoxycytidine (5-Aza-dC) treatment (1-10 uM) depleted DNMT1 in seven of eight pancreatic cancer cell lines. Three of four pancreatic cancers cell lines with low/normal DNMT1 expression were sensitive to growth inhibition by low dose 5-Aza-dC (1 uM), whereas only one of four cell lines with high DNMT1 expression had growth inhibition, and this occurred without evidence of DNMT1 depletion suggesting a different mechanism for growth inhibition in this cell line. Loss of DNMT1 alleles may reduce DNMT1 levels in some pancreatic cancers. Pancreatic cancers with low DNMT1 expression tend to be more sensitive to low-dose 5-aza-dc.

Original languageEnglish (US)
Pages (from-to)321-329
Number of pages9
JournalCancer Biology and Therapy
Volume9
Issue number4
StatePublished - Feb 15 2010

Fingerprint

Pancreatic Neoplasms
Cell Line
Deoxycytidine
Methyltransferases
Growth
Western Blotting
Immunohistochemistry
Alleles
Growth Inhibitors
Pancreatic Ducts
DNA
Chemoprevention
Single Nucleotide Polymorphism
Drug Therapy
Therapeutics

Keywords

  • 5-aza-deoxycytidine
  • DNMT1
  • EGCG
  • Loss of heterozygosity
  • Pancreatic cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

Cite this

Pancreatic cancer DNMT1 expression and sensitivity to DNMT1 inhibitors. / Li, Ang; Omura, Noriyuki; Hong, Seung Mo; Goggins, Michael S.

In: Cancer Biology and Therapy, Vol. 9, No. 4, 15.02.2010, p. 321-329.

Research output: Contribution to journalArticle

Li, Ang ; Omura, Noriyuki ; Hong, Seung Mo ; Goggins, Michael S. / Pancreatic cancer DNMT1 expression and sensitivity to DNMT1 inhibitors. In: Cancer Biology and Therapy. 2010 ; Vol. 9, No. 4. pp. 321-329.
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