Genetic and epigenetic inactivation of Kruppel-like Factor 4 in medulloblastoma

Yukiko Nakahara, Paul A. Northcott, Meihua Li, Paul N. Kongkham, Christian Smith, Hai Yan, Sidney Croul, Young Shin Ra, Charles Eberhart, Annie Huang, Darrell Bigner, Wesia Grajkowska, Timothy Van Meter, James T. Rutka, Michael D. Taylor

Research output: Contribution to journalArticlepeer-review

Abstract

Although medulloblastoma is the most common pediatric malignant brain tumor, its molecular underpinnings are largely unknown. We have identified rare, recurrent homozygous deletions of Kruppel-like Factor 4 (KLF4) in medulloblastoma using high-resolution single nucleotide polymorphism arrays, digital karyotyping, and genomic real-time-polymerase chain reaction (PCR). Furthermore, we show that there is loss of physiological KLF4 expression in more than 40% of primary medulloblastomas both at the RNA and protein levels. Medulloblastoma cell lines drastically increase the expression of KLF4 in response to the demethylating agent 5-azacytidine and demonstrate densemethylation of the promoter CpG island by bisulfite sequencing. Methylation-specific PCR targeting the KLF4 promoter demonstrates CpG methylation in approximately 16% of primary medulloblastomas. Reexpression of KLF4 in the D283 medulloblastoma cell line results in significant growth suppression both in vitro and in vivo. We conclude that KLF4 is inactivated by either genetic or epigenetic mechanismsin a large subset of medulloblastomas and that it likely functions as a tumor suppressor gene in the pathogenesis of medulloblastoma.

Original languageEnglish (US)
Pages (from-to)20-27
Number of pages8
JournalNeoplasia
Volume12
Issue number1
DOIs
StatePublished - Jan 2010

ASJC Scopus subject areas

  • Cancer Research

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