hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing
hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing
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DOI：
10.1172/jci42275
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发表时间：
2010-08-01
影响因子：
15.9
通讯作者：
Juan, Li-Jung
中科院分区：
文献类型：
--
作者：
Lee, Chung-Fan;Ou, Derick S. -C.;Juan, Li-Jung
高甲基化介导的抑癌基因沉默在肿瘤发生中起着至关重要的作用。了解其潜在机制对于癌症治疗至关重要。以前对人N-α-乙酰转移酶10，NatA催化亚基（hNaa 10 p;也称为人抑制缺陷1 [hARD 1]）的研究，就其在肿瘤发生中的作用产生了相互矛盾的结果。在这里，我们提供了多条线索的证据表明，它是致癌的。我们已经证明hNaa 10 p过表达与人肺癌患者的生存率低相关。在体外，hNaa 10 p的强制表达足以引起细胞转化，并且在集落测定和异种移植研究中，siRNA介导的hNaa 10 p消耗损害癌细胞增殖。hNaa 10 p的致癌潜力取决于其与DNA甲基转移酶1（DNMT 1）的相互作用。从机制上讲，hNaa 10 p通过促进其在体外与DNA的结合和在体内向肿瘤抑制基因（如E-钙粘蛋白）的启动子的募集来正向调节DNMT 1的酶活性。与此一致，hNaa 10 p和DNMT 1之间的相互作用是通过启动子CpG甲基化沉默E-钙粘蛋白所必需的，并且E-钙粘蛋白抑制有助于hNaa 10 p的致癌作用。总之，我们的数据不仅建立hNaa 10 p作为一种癌蛋白，但也揭示了它有助于通过调节DNMT 1功能的肿瘤发生。
Hypermethylation-mediated tumor suppressor gene silencing plays a crucial role in tumorigenesis. Understanding its underlying mechanism is essential for cancer treatment. Previous studies on human N-alpha-acetyltransferase 10, NatA catalytic subunit (hNaa10p; also known as human arrest-defective 1 [hARD1]), have generated conflicting results with regard to its role in tumotigenesis. Here we provide multiple lines of evidence indicating that it is oncogenic. We have shown that hNaa10p overexpression correlated with poor survival of human lung cancer patients. In vitro, enforced expression of hNaa10p was sufficient to cause cellular transformation, and siRNA-mediated depletion of hNaa10p impaired cancer cell proliferation in colony assays and xenograft studies. The oncogenic potential of hNaa10p depended on its interaction with DNA methyltransferase 1 (DNMT1). Mechanistically, hNaa10p positively regulated DNMT1 enzymatic activity by facilitating its binding to DNA in vitro and its recruitment to promoters of tumor suppressor genes, such as E-cadherin, in vivo. Consistent with this, interaction between hNaa10p and DNMT1 was required for E-cadherin silencing through promoter CpG methylation, and E-cadhetin repression contributed to the oncogenic effects of hNaa10p. Together, our data not only establish hNaa10p as an oncoprotein, but also reveal that it contributes to oncogenesis through modulation of DNMT1 function.