Upregulation of DNA methyltransferase-mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6

Mol Cancer Res. 2010 Apr;8(4):471-81. doi: 10.1158/1541-7786.MCR-09-0496. Epub 2010 Mar 30.

Abstract

Inflammatory bowel disease is characterized by chronic inflammation which predisposes to colorectal cancer. The mechanisms by which inflammation promotes tumorigenesis are not fully known. We aimed to investigate the links between colonic inflammation and tumorigenesis via epigenetic gene silencing. Colon cancer specimens were assessed for the expression of DNA methyltransferase-1 (DNMT-1) using immunohistochemistry. Colorectal carcinoma cell lines were assessed for DNMT1 expression, methylcytosine content, promoter methylation, gene expression, and tumorigenesis in response to interleukin (IL)-6. DNMT1 was expressed at higher levels in both the peritumoral stroma and tumor in inflammatory bowel disease-associated cancers compared with sporadic colon cancers. IL-6 treatment of colon cancer cells resulted in an increase in DNMT1 expression, independent of de novo gene expression. IL-6 increased the methylation of promoter regions of genes associated with tumor suppression, adhesion, and apoptosis resistance. Expression of a subset of these genes was downregulated by IL-6, an effect that was prevented by preincubation with 5-azadeoxycytidine, a DNMT1 inhibitor. Anchorage-independent growth and migration of colon cancer cells was also increased by IL-6 in a 5-azadeoxycytidine-sensitive manner. Our results indicate that DNMT-mediated gene silencing may play a role in inflammation-associated colon tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Carcinogenicity Tests
  • Carcinoma / enzymology
  • Carcinoma / genetics*
  • Carcinoma / immunology
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Cell Transformation, Neoplastic / metabolism
  • Colitis / enzymology
  • Colitis / genetics*
  • Colitis / immunology
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / immunology
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation / drug effects
  • DNA Methylation / genetics
  • Decitabine
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Enzyme Inhibitors
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Silencing / physiology*
  • Genes, Tumor Suppressor / drug effects
  • Genes, Tumor Suppressor / physiology
  • Humans
  • Immunohistochemistry
  • Inflammation Mediators / metabolism
  • Inflammation Mediators / pharmacology
  • Interleukin-6 / metabolism*
  • Interleukin-6 / pharmacology
  • Neoplasm Metastasis / genetics
  • Promoter Regions, Genetic / genetics
  • Up-Regulation / physiology

Substances

  • Enzyme Inhibitors
  • Inflammation Mediators
  • Interleukin-6
  • Decitabine
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human
  • Azacitidine