Enhanced methyltransferase activity of SMYD3 by the cleavage of its N-terminal region in human cancer cells.
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.
Silva
F Pittella
FP
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Hamamoto
R
R
Kunizaki
M
M
Tsuge
M
M
Nakamura
Y
Y
Furukawa
Y
Y
D000595:Amino Acid Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D045325:HCT116 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary
D009363:Neoplasm Proteins; D010455:Peptides; D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human