64754

SMYD3

SET and MYND domain containing 3;SMYD3;SET and MYND domain containing 3

SET and MYND domain-containing protein 3|bA74P14.1 (novel protein)|histone-lysine N-methyltransferase SMYD3|zinc finger MYND domain-containing protein 1|zinc finger protein, subfamily 3A (MYND domain containing), 1|zinc finger, MYND domain containing 1

1q44

protein-coding

A variable number of tandem repeats (VNTR) polymorphism in regulatory region of SMYD3 coding for histone methyltransferase has been shown to be associated with colorectal cancer, hepatocellular carcinoma (HCC), and breast cancer in Japanese population. Aim of the study is to investigate the potential association between the functional SMYD3 tandem repeats polymorphism and HCC in Chinese population. MATERIAL AND METHODS: The case-control study included 200 HCC patients and 261 healthy controls. The VNTR polymorphism in the promoter of SMDY3 was genotyped by PCR and direct-sequencing analysis. Odds ratio and 95% confidence interval were used to estimate the association between the polymorphisms and risk of HCC. RESULTS: The allele frequencies for SMYD3 2 and 3 repeats were 15.71% and 84.29% among controls; and 12.75%, and 87.25% among cases (P = 0.22). The odds ratio for 3/3 versus 2/2 and 2/3 genotypes was 1.30 (P = 0.18). The frequencies of 3 alleles were not increased with HCC stage increased (trend test, P = 0.45). CONCLUSION: SMYD3 polymorphism is not associated with the occurrence and metastasis of HCC in Chinese population.

Upregulation of the matrix metalloproteinase (MMP)-9 plays a central role in tumor progression and metastasis by stimulating cell migration, tumor invasion, and angiogenesis. To gain insights into MMP-9 expression, we investigated its epigenetic control in a reversible model of cancer that is initiated by infection with intracellular Theileria parasites. Gene induction by parasite infection was associated with trimethylation of histone H3K4 (H3K4me3) at the MMP-9 promoter. Notably, we found that the H3K4 methyltransferase SMYD3 was the only histone methyltransferase upregulated upon infection. SMYD3 is overexpressed in many types of cancer cells, but its contributions to malignant pathophysiology are unclear. We found that overexpression of SMYD3 was sufficient to induce MMP-9 expression in transformed leukocytes and fibrosarcoma cells and that proinflammatory phorbol esters further enhanced this effect. Furthermore, SMYD3 was sufficient to increase cell migration associated with MMP-9 expression. In contrast, RNA interference-mediated knockdown of SMYD3 decreased H3K4me3 modification of the MMP-9 promoter, reduced MMP-9 expression, and reduced tumor cell proliferation. Furthermore, SMYD3 knockdown also reduced cellular invasion in a zebrafish xenograft model of cancer. Together, our results define SMYD3 as an important new regulator of MMP-9 transcription, and they provide a molecular link between SMYD3 overexpression and metastatic cancer progression.