Implication of human N-α-acetyltransferase 5 in cellular proliferation and carcinogenesis
Implication of human N-α-acetyltransferase 5 in cellular proliferation and carcinogenesis
复制标题
DOI：
10.1038/onc.2008.332
复制
发表时间：
2008-12-01
期刊：
影响因子：
8
通讯作者：
Aldabe, R.
中科院分区：
文献类型：
--
作者：
Ametzazurra, A.;Larrea, E.;Aldabe, R.
在酿酒酵母中由Nat 3 p和Mdm 20 p亚基组成的N-α-乙酰基转移酶NatB是酵母生长和对几种胁迫剂的抗性的重要因素。然而，尚未分析哺乳动物对应物的表达和功能作用。在这里，我们报告的Nat 3 p人类同源物（hNAT 5/hNAT 3）的鉴定和其生物学功能的表征。我们发现HeLa细胞中的hNAT 5/hNAT 3沉默导致细胞增殖的抑制和对促凋亡剂MG 132的敏感性增加。此外，hNAT 5/hNAT 3表达的抑制诱导p53活化和抗增殖蛋白p21（WAF 1/CIP 1）的上调。hNAT 5/hNAT 3敲低后细胞转录组的变化证实了该蛋白参与细胞生长和存活过程。在差异表达的基因中，我们观察到几个p53依赖性抗增殖和促凋亡基因的上调。在c-myc转基因小鼠中，这是一种诱导型肝癌模型，我们发现hNAT 5/hNAT 3在肿瘤诱导时上调。根据这一观察结果，我们注意到在高比例的肝细胞癌患者中，肿瘤组织与非肿瘤组织中hNAT 5/hNAT 3蛋白水平升高。因此，我们的研究结果表明，hNAT 5/hNAT 3是细胞增殖所必需的，并可能与肿瘤生长有关。
The N-alpha-acetyltransferase NatB, composed in Saccharomyces cerevisiae by the Nat3p and Mdm20p subunits, is an important factor for yeast growth and resistance to several stress agents. However, the expression and functional role of the mammalian counterpart has not yet been analysed. Here, we report the identification of Nat3p human homologue (hNAT5/hNAT3) and the characterization of its biological function. We found that hNAT5/hNAT3 silencing in HeLa cells results in inhibition of cell proliferation and increased sensitivity to the pro-apoptotic agent MG132. Moreover, inhibition of hNAT5/hNAT3 expression induces p53 activation and upregulation of the antiproliferative protein p21(WAF1/CIP1). The changes of the cellular transcriptome after hNAT5/hNAT3 knockdown confirmed the involvement of this protein in cell growth and survival processes. Among the genes differentially expressed, we observed upregulation of several p53-dependent antiproliferative and pro-apoptotic genes. In the c-myc transgenic mice, which is a model of inducible hepatocarcinoma, we found that hNAT5/hNAT3 was upregulated when the tumour was induced. In accordance with this observation, we noticed increased hNAT5/hNAT3 protein level in neoplastic versus non-neoplastic tissue in a high proportion of patients with hepatocellular carcinoma. Consequently, our results suggest that hNAT5/hNAT3 is required for cellular proliferation and can be implicated in tumour growth.