Kaiso contributes to DNA methylation-dependent silencing of tumor suppressor genes in colon cancer cell lines.
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.
Lopes
Eloisi C
EC
Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Valls
Ester
E
Figueroa
Maria E
ME
Mazur
Alexander
A
Meng
Fan-Guo
FG
Chiosis
Gabriela
G
Laird
Peter W
PW
Schreiber-Agus
Nicole
N
Greally
John M
JM
Prokhortchouk
Egor
E
Melnick
Ari
A
D002453:Cell Cycle / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D045325:HCT116 Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D019941:Cyclin-Dependent Kinase Inhibitor p16; D034741:RNA, Small Interfering; D014157:Transcription Factors; C492254:ZBTB33 protein, human