Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation.
Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation.
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Hdac7 通过抑制 Stat3 激活促进肺部肿瘤发生
DOI：
10.1186/s12943-017-0736-2
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发表时间：
2017-11-10
期刊：
影响因子：
37.3
通讯作者：
Tao W
中科院分区：
文献类型：
--
作者：
Lei Y;Liu L;Zhang S;Guo S;Li X;Wang J;Su B;Fang Y;Chen X;Ke H;Tao W
肺癌是全球癌症死亡的主要原因。然而，肺癌发展的分子机制尚未完全了解。组蛋白去乙酰化酶（HDAC）是使组蛋白和非组蛋白蛋白去乙酰化的总共18种蛋白质（哺乳动物中的HDAC 1 -11和SIRT 1 -7），其在癌症中的功能在很大程度上是未知的。 使用Hdac 7 +/-/K-Ras小鼠和HDAC 7缺失的人肺癌细胞系作为研究Hdac 7基因在肺癌中的功能的模型。Kaplan-Meier生存分析HDAC 7表达与肺癌预后的关系。重组慢病毒介导的体内基因表达或敲低，蛋白质印迹法，和下拉分析，以探讨潜在的分子机制，Hdac 7促进肺肿瘤的发生。与对照K-Ras小鼠相比，Hdac 7 +/−/K-Ras小鼠的肺肿瘤数量和负荷显著降低。此外，在Hdac 7 +/−/K-Ras小鼠中，细胞增殖被显著抑制，肺肿瘤中的细胞凋亡大大增强。同样，表达shHDAC 7的人肺癌细胞系的细胞增殖和锚定非依赖性生长也分别被显著抑制和凋亡显著增加。机制研究表明，小鼠肺肿瘤中的Hdac 7突变或人类肿瘤细胞系中的HDAC 7缺失导致STAT 3和HDAC 7蛋白的乙酰化和酪氨酸磷酸化显着增强，并直接与STAT 3相互作用并脱乙酰化。通过表达dnStat 3分别逆转Hdac 7突变体介导的对小鼠肺肿瘤发生和人肺癌细胞系的细胞增殖/软琼脂集落形成的抑制作用。最后，发现高HDAC 7 mRNA水平与人肺癌患者的不良预后相关。我们的研究表明，Hdac 7通过抑制Stat 3激活通过去乙酰化Stat 3促进肺癌的发生，并可能揭示了新的治疗策略的设计为人类肺癌。本文的在线版本（10.1186/s12943-017-0736-2）包含补充材料，可供授权用户使用。
Lung cancer is the leading cause of cancer death worldwide. However, the molecular mechanisms underlying lung cancer development have not been fully understood. The functions of histone deacetylases (HDACs), a class of total eighteen proteins (HDAC1–11 and SIRT1–7 in mammals) that deacetylate histones and non-histone proteins, in cancers are largely unknown. Hdac7 +/−/K-Ras mice and HDAC7-depleted human lung cancer cell lines were used as models for studying the function of Hdac7 gene in lung cancer. Kaplan-Meier survival analysis was performed to explore the relationship between HDAC7 expression and prognosis of human lung cancers. Recombinant lentivirus-mediated in vivo gene expression or knockdown, Western blotting, and pull-down assay were applied to investigate the underlying molecular mechanism by which Hdac7 promotes lung tumorigenesis. The number and burden of lung tumor were dramatically reduced in Hdac7 +/−/K-Ras mice compared to control K-Ras mice. Also, in Hdac7 +/−/K-Ras mice, cell proliferation was significantly inhibited and apoptosis in lung tumors was greatly enhanced. Similarly, cell proliferation and anchorage-independent growth of human lung cancer cell lines expressing shHDAC7 were also significantly suppressed and apoptosis was dramatically elevated respectively. Mechanistic study revealed that Hdac7 mutation in mouse lung tumors or HDAC7 depletion in human tumor cell lines resulted in significantly enhanced acetylation and tyrosine-phosphorylation of Stat3 and HDAC7 protein directly interacted with and deacetylateed STAT3. The Hdac7 mutant-mediated inhibitory effects on lung tumorigenesis in mice and cell proliferation/soft agar colony formation of human lung cancer cell lines were respectively reversed by expressing dnStat3. Finally, the high HDAC7 mRNA level was found to be correlated with poor prognosis of human lung cancer patients. Our study suggests that Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation via deacetylating Stat3 and may shed a light on the design of new therapeutic strategies for human lung cancer. The online version of this article (10.1186/s12943-017-0736-2) contains supplementary material, which is available to authorized users.
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