The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma.
The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma.
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作者：
Zhou B;Wang Y;Zhang L;Shi X;Kong H;Zhang M;Liu Y;Shao X;Liu Z;Song H;Li W;Gao X;Chang Y;Dou C;Guo W;Zhang S;Kang X;Gao J;Liang Y;Zheng J;Kong E
原理：蛋白质棕榈酰化与肿瘤发生或肿瘤进展密切相关，因为许多癌基因或肿瘤抑制因子都是棕榈酰化的。AEG-1是一种致癌基因，在包括肝细胞癌（HCC）在内的多种人类恶性肿瘤中通常升高。虽然AEG-1被认为可能被蛋白棕榈酰化修饰，但AEG-1棕榈酰化在HCC肿瘤进展中的调节作用尚未被探索。方法：采用Acyl-RAC分析和点突变等技术证实AEG-1确实是棕榈酰化的。此外，生化实验和免疫荧光显微镜应用于检查AEG-1棕榈酰化在几种细胞系的细胞功能。值得注意的是，建立了基因修饰敲入（AEG-1-C75 A）和基因敲除（Zdhhc 6-KO）小鼠，并对其进行DEN处理以诱导HCC小鼠模型，通过该模型直接解决了AEG-1棕榈酰化在HCC中的作用。最后，本文介绍了一种化合物HCQ，从原理上证明了提高AEG-1棕榈酰化水平可能有利于异种移植小鼠肝癌的治疗。结果：我们发现AEG-1在保守的半胱氨酸残基Cys-75上发生棕榈酰化。阻断AEG-1棕榈酰化可加重体内DEN诱导的HCC的进展。此外，已证明AEG-1棕榈酰化受zDHHC 6和PPT 1/2的动态调节。因此，通过缺失Zdhhc 6抑制AEG-1棕榈酰化水平在DEN诱导的HCC小鼠模型中再现了增强的肿瘤进展表型。从机制上讲，我们发现AEG-1棕榈酰化不利地调节其蛋白质的稳定性，并削弱AEG-1和葡萄球菌核酸酶和tudor结构域1（SND 1）的相互作用，这可能有助于RISC活性和肿瘤抑制因子表达的改变。在干预方面，应用一种PPT 1抑制剂HCQ来增加AEG-1棕榈酰化的水平，这延缓了异种移植模型中HCC的肿瘤生长。结论：我们的研究表明AEG-1棕榈酰化动态操纵HCC进展的未知机制，并指出提高AEG-1棕榈酰化可能对HCC的治疗产生有益影响。
Rationale: Protein palmitoylation is tightly related to tumorigenesis or tumor progression as many oncogenes or tumor suppressors are palmitoylated. AEG-1, an oncogene, is commonly elevated in a variety of human malignancies, including hepatocellular carcinoma (HCC). Although AEG-1 was suggested to be potentially modified by protein palmitoylation, the regulatory roles of AEG-1 palmitoylation in tumor progression of HCC has not been explored. Methods: Techniques as Acyl-RAC assay and point mutation were used to confirm that AEG-1 is indeed palmitoylated. Moreover, biochemical experiments and immunofluorescent microscopy were applied to examine the cellular functions of AEG-1 palmitoylation in several cell lines. Remarkably, genetically modified knock-in (AEG-1-C75A) and knockout (Zdhhc6-KO) mice were established and subjected to the treatment of DEN to induce the HCC mice model, through which the roles of AEG-1 palmitoylation in HCC is directly addressed. Last, HCQ, a chemical compound, was introduced to prove in principal that elevating the level of AEG-1 palmitoylation might benefit the treatment of HCC in xenograft mouse model. Results: We showed that AEG-1 undergoes palmitoylation on a conserved cysteine residue, Cys-75. Blocking AEG-1 palmitoylation exacerbates the progression of DEN-induced HCC in vivo. Moreover, it was demonstrated that AEG-1 palmitoylation is dynamically regulated by zDHHC6 and PPT1/2. Accordingly, suppressing the level of AEG-1 palmitoylation by the deletion of Zdhhc6 reproduces the enhanced tumor-progression phenotype in DEN-induced HCC mouse model. Mechanistically, we showed that AEG-1 palmitoylation adversely regulates its protein stability and weakens AEG-1 and staphylococcal nuclease and tudor domain containing 1 (SND1) interaction, which might contribute to the alterations of the RISC activity and the expression of tumor suppressors. For intervention, HCQ, an inhibitor of PPT1, was applied to augment the level of AEG-1 palmitoylation, which retards the tumor growth of HCC in xenograft model. Conclusion: Our study suggests an unknown mechanism that AEG-1 palmitoylation dynamically manipulates HCC progression and pinpoints that raising AEG-1 palmitoylation might confer beneficial effect on the treatment of HCC.
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影响因子：
3.6
作者：
Heakal, Yasser;Woll, Matthew P.;Kester, Mark
通讯作者：
Kester, Mark
影响因子：
64.8
作者：
Chen S;Zhu B;Yin C;Liu W;Han C;Chen B;Liu T;Li X;Chen X;Li C;Hu L;Zhou J;Xu ZX;Gao X;Wu X;Goding CR;Cui R
通讯作者：
Cui R
影响因子：
3.5
作者：
Fairbank, Maria;Huang, Kun;Nabi, Ivan R.
通讯作者：
Nabi, Ivan R.
DOI：
10.1158/1078-0432.ccr-09-0049
发表时间：
2009-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hu G;Wei Y;Kang Y
通讯作者：
Kang Y
影响因子：
5.3
作者：
Kaur, Inderpreet;Yarov-Yarovoy, Vladimir;Diaz, Elva
通讯作者：
Diaz, Elva