Tumor Necrosis Factor Receptor-Associated Factor 6 Promotes Hepatocarcinogenesis by Interacting With Histone Deacetylase 3 to Enhance c-Myc Gene Expression and Protein Stability
Tumor Necrosis Factor Receptor-Associated Factor 6 Promotes Hepatocarcinogenesis by Interacting With Histone Deacetylase 3 to Enhance c-Myc Gene Expression and Protein Stability
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肿瘤坏死因子受体相关因子 6 通过与组蛋白脱乙酰酶 3 相互作用增强 c-Myc 基因表达和蛋白质稳定性促进肝癌发生
DOI：
10.1002/hep.30801
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发表时间：
2019-08-07
期刊：
影响因子：
13.5
通讯作者：
Li, Jian-Ming
中科院分区：
文献类型：
--
作者：
Wu, Hua;Yang, Tian-Yu;Li, Jian-Ming
癌基因c-Myc的异常表达在肝细胞癌（HCC）的恶性转化和进展中起关键作用。在这里，我们报告说，c-Myc是显着上调肿瘤坏死因子受体相关因子6（TRAF 6），E3泛素连接酶，在肝癌的发生。临床HCC样本中TRAF 6的高表达与不良预后相关，Traf 6（+/-）小鼠中Traf 6基因的一个拷贝的丢失显著损害肝脏肿瘤发生。在机制上，TRAF 6首先与具有K63连接的泛素链的组蛋白去乙酰化酶3（HDAC 3）相互作用并使其泛素化，这导致HDAC 3从c-Myc启动子解离，随后在K9处乙酰化组蛋白H3，从而在表观遗传学上增强c-Myc的mRNA表达。其次，HDAC 3的K63连接的泛素化损害HDAC 3与c-Myc的相互作用并促进c-Myc蛋白乙酰化，从而通过抑制热休克同源70-kDa相互作用蛋白介导的c-Myc泛素化和降解的羧基末端来增强c-Myc蛋白的稳定性。重要的是，TRAF 6/HDAC 3/c-Myc信号传导也在B肝炎病毒转基因小鼠中启动，揭示了炎症-癌症转变机制的关键作用。在临床标本中，TRAF 6与c-Myc在mRNA和蛋白水平上均呈正相关，TRAF 6和c-Myc的高表达与不良预后相关，表明TRAF 6与c-Myc协同促进人类肝癌的发生。一致地，通过用TRAF 6抑制剂肽抑制TRAF 6活性或通过小干扰RNA沉默c-Myc来抑制c-Myc表达显著抑制了小鼠中的肿瘤生长。结论：这些发现表明TRAF 6在肝癌发生过程中通过调节TRAF 6/HDAC 3/c-Myc信号传导具有致癌潜力，对HCC治疗具有潜在意义。
The oncogene c-Myc is aberrantly expressed and plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). Here, we report that c-Myc is significantly up-regulated by tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, in hepatocarcinogenesis. High TRAF6 expression in clinical HCC samples correlates with poor prognosis, and the loss of one copy of the Traf6 gene in Traf6(+/-) mice significantly impairs liver tumorigenesis. Mechanistically, TRAF6 first interacts with and ubiquitinates histone deacetylase 3 (HDAC3) with K63-linked ubiquitin chains, which leads to the dissociation of HDAC3 from the c-Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c-Myc. Second, the K63-linked ubiquitination of HDAC3 impairs the HDAC3 interaction with c-Myc and promotes c-Myc protein acetylation, which thereby enhances c-Myc protein stability by inhibiting carboxyl terminus of heat shock cognate 70-kDa-interacting protein-mediated c-Myc ubiquitination and degradation. Importantly, TRAF6/HDAC3/c-Myc signaling is also primed in hepatitis B virus-transgenic mice, unveiling a critical role for a mechanism in inflammation-cancer transition. In clinical specimens, TRAF6 positively correlates with c-Myc at both the mRNA and protein levels, and high TRAF6 and c-Myc expression is associated with an unfavorable prognosis, suggesting that TRAF6 collaborates with c-Myc to promote human hepatocarcinogenesis. Consistently, curbing c-Myc expression by inhibition of TRAF6 activity with a TRAF6 inhibitor peptide or the silencing of c-Myc by small interfering RNA significantly suppressed tumor growth in mice. Conclusion: These findings demonstrate the oncogenic potential of TRAF6 during hepatocarcinogenesis by modulating TRAF6/HDAC3/c-Myc signaling, with potential implications for HCC therapy.