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Oncogene. 2008 Apr 24;27(19):2686-92. Epub 2007 Nov 12.

Enhanced methyltransferase activity of SMYD3 by the cleavage of its N-terminal region in human cancer cells.

Author information

1
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Abstract

Histone methylation is involved in the regulation of gene expression and DNA replication through alteration of chromatin structure. We earlier showed that SMYD3, a histone H3-lysine 4-specific methyltransferase, is frequently upregulated in human colorectal, liver and breast cancer compared to their matched non-cancerous cells, and that its activity is associated with the growth of these tumors. In the present study, we found that human cancer cells express both the full-length and a cleaved form of SMYD3 protein. Amino acid sequence analysis uncovered that the cleaved form lacks the 34 amino acids in the N-terminal region of the full-length protein. Interestingly, the cleaved protein and mutant protein containing substitutions at glycines 15 and 17, two highly conserved amino acids in the N-terminal region, revealed a higher histone methyltransferase (HMTase) activity compared to the full-length protein. Furthermore, the N-terminal region is responsible for the association with heat shock protein 90alpha (HSP90alpha). These data indicate that the N-terminal region plays an important role for the regulation of its methyltransferase activity and suggest that a structural change of the protein through the cleavage of the region or interaction with HSP90alpha may be involved in the modulation. These findings may help for a better understanding of the mechanisms that modulate the HMTase activity of SMYD3, and contribute to the development of novel anticancer drugs targeting SMYD3 methyltransferase activity.

PMID:
17998933
DOI:
10.1038/sj.onc.1210929
[Indexed for MEDLINE]

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