title: A variable number of tandem repeats polymorphism in an E2F-1 binding element in the 5' flanking region of SMYD3 is a risk factor for human cancers.
abstract: Histone modification is a crucial step in transcriptional regulation, and deregulation of the modification process is important in human carcinogenesis. We previously reported that upregulation of SMYD3, a histone methyltransferase, promoted cell growth in human colorectal and hepatocellular carcinomas. Here we report significant associations between homozygosity with respect to an allele with three tandem repeats of a CCGCC unit in the regulatory region of SMYD3 and increased risk of colorectal cancer (P = 9.1 x 10(-6), odds ratio = 2.58), hepatocellular carcinoma (P = 2.3 x 10(-8), odds ratio = 3.50) and breast cancer (P = 7.0 x 10(-10), odds ratio = 4.48). This tandem-repeat sequence is a binding site for the transcriptional factor E2F-1. In a reporter assay, plasmids containing three repeats of the binding motif (corresponding to the high-risk allele) had higher activity than plasmids containing two repeats (the low-risk allele). These data suggest that the common variable number of tandem repeats polymorphism in SMYD3 is a susceptibility factor for some types of human cancer.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Tsuge
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
authors.forename: Fabio Pittella
authors.initials: FP
authors.lastname: Silva
authors.forename: Yozo
authors.initials: Y
authors.lastname: Ohnishi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D024506:5' Flanking Region / Q000235:genetics; D000483:Alleles; D001483:Base Sequence; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D020080:Tandem Repeat Sequences / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D050687:E2F1 Transcription Factor; D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human