SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells
SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells
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DOI：
10.1038/ncb1151
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发表时间：
2004-08-01
影响因子：
21.3
通讯作者：
Nakamura, Y
中科院分区：
文献类型：
--
作者：
Hamamoto, R;Furukawa, Y;Nakamura, Y
结直肠癌和肝细胞癌是世界范围内癌症死亡的主要原因之一，但这些恶性肿瘤的潜在机制尚未完全了解。在这里，我们报告的SMYD 3，在大多数结直肠癌和肝细胞癌中过度表达的基因的鉴定。将SMYD 3引入NIH 3 T3细胞中增强了细胞生长，而在癌细胞中用小干扰RNA（siRNA）进行基因敲低导致显著的生长抑制。SMYD 3通过与RNA解旋酶HELZ的相互作用与RNA聚合酶II形成复合物，并反式激活一组基因，包括癌基因、同源框基因和与细胞周期调控相关的基因。SMYD 3与存在于下游基因如Nkx2.8的启动子区的基序5 '-CCCTCC-3'结合。SMYD 3的SET结构域显示组蛋白H3-赖氨酸4（H3-K4）特异性甲基转移酶活性，其在热休克蛋白HSP 90 A存在下增强。我们的研究结果表明，SMYD 3具有组蛋白甲基转移酶活性，并作为RNA聚合酶复合物的一员在转录调控中发挥重要作用。此外，SMYD 3的激活可能是人类致癌的关键因素。
Colorectal and hepatocellular carcinomas are some of the leading causes of cancer deaths worldwide, but the mechanisms that underly these malignancies are not fully understood. Here we report the identification of SMYD3, a gene that is over-expressed in the majority of colorectal carcinomas and hepatocellular carcinomas. Introduction of SMYD3 into NIH3T3 cells enhanced cell growth, whereas genetic knockdown with small-interfering RNAs (siRNAs) in cancer cells resulted in significant growth suppression. SMYD3 formed a complex with RNA polymerase II through an interaction with the RNA helicase HELZ and transactivated a set of genes that included oncogenes, homeobox genes and genes associated with cell-cycle regulation. SMYD3 bound to a motif, 5'-CCCTCC-3', present in the promoter region of downstream genes such as Nkx2.8. The SET domain of SMYD3 showed histone H3-lysine 4 (H3-K4)-specific methyltransferase activity, which was enhanced in the presence of the heat-shock protein HSP90A. Our findings suggest that SMYD3 has histone methyltransferase activity and plays an important role in transcriptional regulation as a member of an RNA polymerase complex. Furthermore, activation of SMYD3 may be a key factor in human carcinogenesis.