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A Requirement for DICER to Maintain Full Promoter CpG Island Hypermethylation in Human Cancer Cells

¹ Genomic Medicine Institute, Lerner Research Institute, Cleveland, Ohio; ² First Department of Internal Medicine, and ³ Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Chuo-ku, Japan; and ⁴ Biometry and Clinical Trials Division, ⁵ Cancer Biology Division, and ⁶ The Johns Hopkins Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Angela H. Ting, Cleveland Clinic Foundation. E-mail: tinga{at}ccf.org or Hiromu Suzuki, Sapporo Medical University. E-mail: hsuzuki{at}sapmed.ac.jp or Stephen B. Baylin, Bunting Blaustein Cancer Center, The Johns Hopkins University, 1650 Orleans Street, Suite 541, Baltimore, MD 21231. Phone: 410-955-8506; Fax: 410-614-9984; E-mail: sbaylin{at}jhmi.edu.

Key Words: epigenetics • DICER • promoter hypermethylation • cancer

Promoter hypermethylation is a prevalent phenomenon, found in virtually all cancer types studied thus far, and accounts for tumor suppressor gene silencing in the absence of genetic mutations. The mechanism behind the establishment and maintenance of such aberrant hypermethylation has been under intense study. Here, we have uncovered a link between aberrant gene silencing associated with promoter CpG island DNA methylation and the siRNA/miRNA processing enzyme, DICER, in human cancer cells. By comparing demethylated HCT116 colon cancer cells with HCT116 cells genetically rendered hypomorphic for DICER, we identified a group of epigenetically silenced genes that became reactivated in the absence of functional DICER. This reactivation is associated with a dramatic loss of localized promoter DNA hypermethylation. Thus, intact DICER is required to maintain full promoter DNA hypermethylation of select epigenetically silenced loci in human cancer cells. [Cancer Res 2008;68(8):2570–5]

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