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首页> 外文期刊>Oncogene >Enhanced methyltransferase activity of SMYD3 by the cleavage of its N-terminal region in human cancer cells
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Enhanced methyltransferase activity of SMYD3 by the cleavage of its N-terminal region in human cancer cells

机译：通过在人类癌细胞中切割其N末端区域增强SMYD3的甲基转移酶活性

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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 90α (HSP90α). 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 HSP90α 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.
机译：组蛋白甲基化通过染色质结构的改变参与基因表达和DNA复制的调控。我们较早的研究表明，与匹配的非癌细胞相比，组蛋白H3-赖氨酸4特异性甲基转移酶SMYD3在人大肠癌，肝癌和乳腺癌中经常被上调，并且其活性与这些肿瘤的生长有关。在本研究中，我们发现人类癌细胞表达SMYD3蛋白的全长和裂解形式。氨基酸序列分析发现，切割的形式在全长蛋白质的N末端区域缺少34个氨基酸。有趣的是，裂解蛋白和突变蛋白在甘氨酸15和17处具有取代基，在N端区域有两个高度保守的氨基酸，与全长蛋白相比，具有更高的组蛋白甲基转移酶（HMTase）活性。此外，N末端区域负责与热激蛋白90α（HSP90α）的缔合。这些数据表明，N-末端区域对其甲基转移酶活性的调节起着重要作用，并表明通过该区域的切割或与HSP90α的相互作用，蛋白质的结构变化可能参与了调节。这些发现可能有助于更好地理解调节SMYD3的HMTase活性的机制，并有助于开发靶向SMYD3甲基转移酶活性的新型抗癌药物。

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