Differential promoter methylation may be a key molecular mechanism in regulating BubR1 expression in cancer cells.
- Author:
Hye Young PARK
1
;
Yoon Kyung JEON
;
Hyun Jin SHIN
;
Il Jin KIM
;
Hio Chung KANG
;
Sook Jung JEONG
;
Doo Hyun CHUNG
;
Chang Woo LEE
Author Information
1. Department of Molecular Cell Biology Center for Molecular Medicine Samsung Biomedical Research Institute Sungkyunkwan University School of Medicine, Suwon 440-746, Korea. cwlee@med.skku.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
Bub1 spindle checkpoint protein;
colorectal neoplasms;
DNA methylation;
polymorphism, genetic
- MeSH:
Azacitidine/pharmacology;
Base Sequence;
Cell Line, Tumor;
*DNA Methylation/drug effects;
DNA Mutational Analysis;
DNA-Binding Proteins/metabolism;
*Gene Expression Regulation, Neoplastic/drug effects;
Hela Cells;
Histone Deacetylases/metabolism;
Humans;
Jurkat Cells;
Molecular Sequence Data;
Neoplasms/*genetics/*pathology;
Polymorphism, Genetic/drug effects;
Promoter Regions, Genetic/drug effects/*genetics;
Protein Binding/drug effects;
Protein Kinases/*genetics;
Protein-Serine-Threonine Kinases;
Transcription, Genetic/drug effects
- From:Experimental & Molecular Medicine
2007;39(2):195-204
- CountryRepublic of Korea
- Language:English
-
Abstract:
The BubR1 mitotic-checkpoint protein monitors proper attachment of microtubules to kinetochores, and links regulation of chromosome-spindle attachment to mitotic-checkpoint signaling. Thus, disruption of BubR1 activity results in a loss of checkpoint control, chromosomal instability caused by a premature anaphase, and/or the early onset of tumorigenesis. The mechanisms by which deregulation and/or abnormalities of BubR1 expression operate, however, remain to be elucidated. In this study, we demonstrate that levels of BubR1 expression are significantly increased by demethylation. Bisulfite sequencing analysis revealed that the methylation status of two CpG sites in the essential BubR1 promoter appear to be associated with BubR1 expression levels. Associations of MBD2 and HDAC1 with the BubR1 promoter were significantly relieved by addition of 5-aza-2'-deoxycytidine, an irreversible DNA methyltransferase inhibitor. However, genomic DNA isolated from 31 patients with colorectal carcinomas exhibited a +84A/G polymorphic change in approximately 60% of patients, but this polymorphism had no effect on promoter activity. Our findings indicate that differential regulation of BubR1 expression is associated with changes in BubR1 promoter hypermethylation patterns, but not with promoter polymorphisms, thus providing a novel insight into the molecular regulation of BubR1 expression in human cancer cells.
