Kaiso contributes to DNA methylation-dependent silencing of tumor suppressor genes in colon cancer cell lines

Eloisi C. Lopes, Ester Valls, Maria E. Figueroa, Alexander Mazur, Fan Guo Meng, Gabriela Chiosis, Peter W. Laird, Nicole Schreiber-Agus, John M. Greally, Egor Prokhortchouk, Ari Melnick

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7258-7263
Number of pages6
JournalCancer Research
Volume68
Issue number18
DOIs
StatePublished - Sep 15 2008
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Lopes, E. C., Valls, E., Figueroa, M. E., Mazur, A., Meng, F. G., Chiosis, G., Laird, P. W., Schreiber-Agus, N., Greally, J. M., Prokhortchouk, E., & Melnick, A. (2008). Kaiso contributes to DNA methylation-dependent silencing of tumor suppressor genes in colon cancer cell lines. Cancer Research, 68(18), 7258-7263. https://doi.org/10.1158/0008-5472.CAN-08-0344