Ametzazurra A, Larrea E, Civeira M P, Prieto J, Aldabe R
Division of Hepatology and Gene Therapy, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Oncogene. 2008 Dec 11;27(58):7296-306. doi: 10.1038/onc.2008.332. Epub 2008 Sep 15.
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.
N-α-乙酰基转移酶NatB在酿酒酵母中由Nat3p和Mdm20p亚基组成，是酵母生长及对多种应激因子抗性的重要因素。然而，其哺乳动物对应物的表达及功能作用尚未得到分析。在此，我们报告了Nat3p人类同源物（hNAT5/hNAT3）的鉴定及其生物学功能的表征。我们发现，HeLa细胞中hNAT5/hNAT3的沉默导致细胞增殖受到抑制，并增加了对促凋亡剂MG132的敏感性。此外，hNAT5/hNAT3表达的抑制诱导了p53的激活以及抗增殖蛋白p21（WAF1/CIP1）的上调。hNAT5/hNAT3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。在可诱导肝癌模型的c-myc转基因小鼠中，我们发现肿瘤诱导时hNAT5/hNAT3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相比hNAT5/hNAT3蛋白水平升高。因此，我们的结果表明hNAT5/hNAT3是细胞增殖所必需的，并且可能与肿瘤生长有关。
