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

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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 × 10−6, odds ratio = 2.58), hepatocellular carcinoma (P = 2.3 × 10−8, odds ratio = 3.50) and breast cancer (P = 7.0 × 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.