Epigenetic regulation of c-ROS receptor tyrosine kinase expression in malignant gliomas

Cancer Res. 2009 Mar 15;69(6):2180-4. doi: 10.1158/0008-5472.CAN-08-3351. Epub 2009 Mar 10.

Abstract

The proto-oncogene tyrosine kinase c-ROS is an orphan receptor whose normal expression pattern is tightly spatio-temporally restricted during development. In glioma, c-ROS mRNA expression is frequently ectopically up-regulated. In this study, we determined by immunohistochemical means that c-ROS receptor protein is present in 25% of low-grade and 30% of malignant glioma tumor samples from tissue microarrays. We then explored the molecular basis for the up-regulation of c-ROS expression in these tumors. We identified and characterized the c-ROS gene promoter region and report that the ectopic expression of c-ROS in tumors is tied to hypomethylation of a CpG island in the c-ROS promoter. Bisulfite sequencing analysis in glioma tumor samples revealed that demethylation of the CpG island (-384 to -132 bp) correlated with c-ROS expression. Moreover, c-ROS expression could be activated by treatment of c-ROS-negative cells with the demethylating agent 5-aza-2'-deoxycytidine. These results establish a strong link between c-ROS promoter demethylation and gain of c-ROS expression and function in glioma. Our data suggest that epigenetic activation of c-ROS represents an important oncogenic mechanism for glioma initiation and progression and suggest that cautionary measures in the clinical use of 5-aza-dC for the treatment of glioma be taken into consideration. [Cancer Res 2009;69(6):2180-4].

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytoma / drug therapy
  • Astrocytoma / enzymology*
  • Astrocytoma / genetics*
  • Astrocytoma / pathology
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • DNA Methylation
  • Decitabine
  • Disease Progression
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Microarray Analysis
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptor Protein-Tyrosine Kinases / biosynthesis*
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Tumor Cells, Cultured
  • Up-Regulation

Substances

  • RNA, Messenger
  • Decitabine
  • Receptor Protein-Tyrosine Kinases
  • Azacitidine