Black raspberry-derived anthocyanins demethylate tumor suppressor genes through the inhibition of DNMT1 and DNMT3B in colon cancer cells

Nutr Cancer. 2013;65(1):118-25. doi: 10.1080/01635581.2013.741759.

Abstract

We previously reported that oral administration of black raspberry powder decreased promoter methylation of tumor suppressor genes in tumors from patients with colorectal cancer. The anthocyanins (ACs) in black raspberries are responsible, at least in part, for their cancer-inhibitory effects. In the present study, we asked if ACs are responsible for the demethylation effects observed in colorectal cancers. Three days of treatment of ACs at 0.5, 5, and 25 μg/ml suppressed activity and protein expression of DNMT1 and DNMT3B in HCT116, Caco2 and SW480 cells. Promoters of CDKN2A, and SFRP2, SFRP5, and WIF1, upstream of Wnt pathway, were demethylated by ACs. mRNA expression of some of these genes was increased. mRNA expression of β-catenin and c-Myc, downstream of Wnt pathway, and cell proliferation were decreased; apoptosis was increased. ACs were taken up into HCT116 cells and were differentially localized with DNMT1 and DNMT3B in the same cells visualized using confocal laser scanning microscopy. Although it was reported that DNMT3B is regulated by c-Myc in mouse lymphoma, DNMT3B did not bind with c-Myc in HCT116 cells. In conclusion, our results suggest that ACs are responsible, at least in part, for the demethylation effects of whole black raspberries in colorectal cancers.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Anthocyanins / pharmacology*
  • Caco-2 Cells / drug effects
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism*
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors*
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation
  • Enzyme Inhibitors / pharmacology
  • Eye Proteins / genetics
  • Genes, Tumor Suppressor / drug effects*
  • Genes, p16
  • Humans
  • Membrane Proteins / genetics
  • Promoter Regions, Genetic / drug effects
  • Repressor Proteins / genetics
  • Rosaceae / chemistry*

Substances

  • Adaptor Proteins, Signal Transducing
  • Anthocyanins
  • Enzyme Inhibitors
  • Eye Proteins
  • Membrane Proteins
  • Repressor Proteins
  • SFRP2 protein, human
  • SFRP5 protein, human
  • WIF1 protein, human
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3B
  • DNMT1 protein, human
  • Dnmt1 protein, mouse