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Kaiso Contributes to DNA Methylation-Dependent Silencing of Tumor Suppressor Genes in Colon Cancer Cell Lines

¹ Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center; ² Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York; Departments of ³ Developmental and Molecular Biology and ⁴ Medicine and Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York; ⁵ Center "Bioengineering", Moscow, Russian Federation; and ⁶ Departments of Surgery and of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California

Requests for reprints: Ari Melnick, Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065. Phone: 212-746-7643; Fax: 212-746-8866; E-mail: amm2014{at}med.cornell.edu or Egor Prokhortchouk, Center "Bioengineering," 60-let Oktyabrya 7-1, 117312, Moscow, Russian Federation. E-mail: prokhortchouk{at}biengi.ac.ru.

Key Words: Kaiso • Transcriptional repression • DNA methylation • epigenetic silencing • colon cancer

Aberrant CpG methylation of tumor suppressor gene regulatory elements is associated with transcriptional silencing and contributes to malignant transformation of different tissues. It is presumed that methylated DNA sequences recruit repressor machinery to actively shutdown gene expression. The Kaiso protein is a transcriptional repressor expressed in human and murine colorectal tumors that can bind to methylated clusters of CpG dinucleotides. We show here that Kaiso represses methylated tumor suppressor genes and can bind in a methylation-dependent manner to the CDKN2A in human colon cancer cell lines. The contribution of Kaiso to epigenetic silencing was underlined by the fact that Kaiso depletion induced tumor suppressor gene expression without affecting DNA methylation levels. As a consequence, colon cancer cells became susceptible to cell cycle arrest and cell death mediated by chemotherapy. The data suggest that Kaiso is a methylation-dependent "opportunistic" oncogene that silences tumor suppressor genes when they become hypermethylated. Because Kaiso inactivation sensitized colon cancer cell lines to chemotherapy, it is possible that therapeutic targeting of Kaiso could improve the efficacy of current treatment regimens. [Cancer Res 2008;68(18):7258–63]

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