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Abnormal DNA Methylation of CD133 in Colorectal and Glioblastoma Tumors

¹ Cancer Biology Division, Johns Hopkins Kimmel Cancer Center; ² Graduate Program in Cellular and Molecular Medicine, ³ Department of Surgery, ⁴ Department of Pathology, and ⁵ The Kennedy-Krieger Institute and Department of Neurology, Johns Hopkins University School of Medicine; ⁶ Department of Radiation Oncology and Molecular Radiation Sciences, The Sydney Kimmel Comprehensive Cancer Center; ⁷ Department of Neurosurgery, Johns Hopkins University Medical School, Baltimore, Maryland; ⁸ Brain Tumor Research Center, Department of Neurological Surgery, University of California at San Francisco, San Francisco, California; and ⁹ Department of Biotechnology and Biosciences, University of Milan Bicocca, Milan, Italy

Requests for reprints: Stephen B. Baylin, Johns Hopkins University, Bunting Blaustein Cancer Center, 1650 Orleans Street, Suite 541, Baltimore, MD 21231. Phone: 410-955-8506; Fax: 410-614-9984; E-mail: sbaylin{at}jhmi.edu.

Key Words: CD133 • DNA methylation • tumor propagating cells (TPC) • histone modifications • cancer

Much recent effort has focused on identifying and characterizing cellular markers that distinguish tumor propagating cells (TPC) from more differentiated progeny. We report here an unusual promoter DNA methylation pattern for one such marker, the cell surface antigen CD133 (Prominin 1). This protein has been extensively used to enrich putative cancer propagating stem-like cell populations in epithelial tumors and, especially, glioblastomas. We find that, within individual cell lines of cultured colon cancers and glioblastomas, the promoter CpG island of CD133 is DNA methylated, primarily, in cells with absent or low expression of the marker protein, whereas lack of such methylation is evident in purely CD133+ cells. Differential histone modification marks of active versus repressed genes accompany these DNA methylation changes. This heterogeneous CpG island DNA methylation status in the tumors is unusual in that other DNA hypermethylated genes tested in such cultures preserve their methylation patterns between separated CD133+ and CD133– cell populations. Furthermore, the CD133 DNA methylation seems to constitute an abnormal promoter signature because it is not found in normal brain and colon but only in cultured and primary tumors. Thus, the DNA methylation is imposed on the transition between the active versus repressed transcription state for CD133 only in tumors. Our findings provide additional insight for the dynamics of aberrant DNA methylation associated with aberrant gene silencing in human tumors. [Cancer Res 2008;68(19):8094–103]

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