Chromodomain Helicase/Adenosine Triphosphatase DNA Binding Protein 1-Like (CHD1L) Gene Suppresses the Nucleus-to-Mitochondria Translocation of Nur77 to Sustain Hepatocellular Carcinoma Cell Survival
Chromodomain Helicase/Adenosine Triphosphatase DNA Binding Protein 1-Like (CHD1L) Gene Suppresses the Nucleus-to-Mitochondria Translocation of Nur77 to Sustain Hepatocellular Carcinoma Cell Survival
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DOI：
10.1002/hep.22933
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发表时间：
2009-07-01
期刊：
影响因子：
13.5
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Chen, Leilei;Hu, Liang;Guan, Xin-Yuan
在58%至78%的原发性肝细胞癌病例中检测到1 q21扩增，这表明扩增子中的一个或多个癌基因在这种疾病的发展中起关键作用。chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like gene（CHD 1 L）是最近发现的一个位于1 q21的癌基因。我们以前的研究表明，CHD 1 L具有很强的致瘤能力，并赋予CHD 1 L转基因小鼠模型自发性肿瘤的高易感性。在这项研究中，我们证明了CHD 1 L的抗凋亡能力与其与Nur 77的相互作用有关，Nur 77是p53非依赖性凋亡途径的关键成员。CHD 1 L作为第一个被鉴定为与Nur 77结合的细胞蛋白，能够抑制Nur 77的核-线粒体转位，从而阻碍细胞色素c的释放，启动细胞凋亡。通过RNA干扰敲低CHD 1 L表达可以拯救Nur 77的线粒体靶向作用和随后的凋亡。进一步的研究发现，CHD 1 L的C-末端Macro结构域负责与Nur 77的相互作用，并且缺失残基600-897的CHD 1 L突变体不能与Nur 77相互作用并且阻止Nur 77介导的凋亡。更重要的是，我们发现内源性CHD 1 L抑制Nur 77介导的细胞凋亡是肝癌发生的关键生物细胞过程。结论：我们在这项研究中证明，CHD 1 L的过表达可以通过阻止Nur 77介导的凋亡来维持肿瘤细胞的存活。（《肝脏病学》2009年;50：122-129。）
Amplification of 1q21 has been detected in 58% to 78% of primary hepatocellular carcinoma cases, suggesting that one or more oncogenes within the amplicon play a critical role in the development of this disease. The chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like gene (CHD1L) is a recently identified oncogene localized at 1q21. Our previous studies have demonstrated that CHD1L has strong tumorigenic ability and confers high susceptibility to spontaneous tumors in a CHD1L-transgenic mouse model. In this study, we demonstrate that the antiapoptotic ability of CHD1L is associated with its interaction with Nur77, a critical member of a p53-independent apoptotic pathway. As the first cellular protein identified to bind Nur77, CHD1L is able to inhibit the nucleus-to-mitochondria translocation of Nur77, which is the key step of Nur77-mediated apoptosis, resulting in the hindrance of the release of cytochrome c and the initiation of apoptosis. Knock-down of CHD1L expression by RNA interference could rescue the mitochondrial targeting of Nur77 and the subsequent apoptosis. Further studies found that the C-terminal Macro domain of CHD1L is responsible for the interaction with Nur77, and a CHD1L mutant lacking residues 600-897 failed to interact with Nur77 and prevented Nur77-mediated apoptosis. More importantly, we found that the inhibition of Nur77-mediated apoptosis by endogenous CHD1L is a critical biological cellular process in hepatocarcinogenesis. Conclusion: We demonstrate in this study that overexpression of CHD1L could sustain tumor cell survival by preventing Nur77-mediated apoptosis. (HEPATOLOGY 2009;50:122-129.)