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

Hyun G. Jun, Steve Woolfenden, Shanie Coven, Keara Michelle Lane, Roderick Bronson, David Housman, Alan Charest*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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 hypomethy- lation 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'-deoxyeytidine. 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.

Original languageEnglish (US)
Pages (from-to)2180-2184
Number of pages5
JournalCancer Research
Volume69
Issue number6
DOIs
StatePublished - Mar 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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