HDAC7/HSF1通路调控内质网应激驱动肺腺癌恶性进展的研究

Histone deacetylase 7 (HDAC7), a proliferation-related endogenous factor, involves in the progression of various tumors. The recent study and our research results documented HDAC7 is overexpressed in the lung adenocarcinoma tissues, but the mechanisms remain unclear. Recently, our preliminary experiments documented HDAC7 overexpression promoted the proliferation in lung adenocarcinoma cells and nude mice-bearing tumors, and significantly inhibited the expression of ERS-related signaling pathways and partially upregulated the expression of heat shock proteins (HSPs). Considering deacylated heat shock factor 1 (HSF1) promotes the HSPs expression, which contributes to the regulation of ERS signaling and maintenance of endoplasmic reticulum homeostasis, we put forward the scientific hypothesis that ERS is regulated by the HDAC7-induced HSF1 deacylation then promoting the lung adenocarcinoma progression. On the above bases, lung adenocarcinoma cell lines and nude bearding mice models will be used to investigate the underlining mechanisms of HDAC7-HSF1/HSPs signaling in regulating ERS pathways thus promoting lung adenocarcinoma progression both in vivo and in vitro. In the meantime, we will comprehensively analyze the correlation between these signaling and clinical prognosis using lung adenocarcinoma patient’s tissues. Above all, this study will provide new anti-cancer method and theoretical basis for targeting HDAC7-HSF1 signaling pathway during lung adenocarcinoma treatment.

组蛋白去乙酰化酶7（HDAC7）是重要的促增殖因子，在肿瘤恶性进展中起重要作用。最新文献和我们研究表明HDAC7在肺腺癌组织中高表达，但其作用及机制尚未阐明。前期结果显示HDAC7过表达可显著促进肺腺癌细胞增殖和移植瘤生长，并发现内质网应激（ERS）信号通路相关分子表达下调和热休克蛋白（HSPs）表达上调。鉴于热休克因子1（HSF1）去乙酰化后上调HSPs在维持内质网稳态中发挥重要作用，我们推测HDAC7在肺腺癌中可能通过去乙酰化HSF1调控ERS发挥促肿瘤进展作用。为此，本项目拟从临床标本、裸鼠荷瘤模型、细胞与分子水平，进一步明确HDAC7高表达促进肺腺癌进展的作用；阐明HSF1/HSPs通路在介导HDAC7调控ERS促肺腺癌进展的具体机制；结合临床资料和标本综合分析这些因子表达水平与临床预后的相关性。本研究的完成将为开发靶向HDAC7-HSF1信号通路抗肺腺癌的方法或药物奠定理论基础。

背景:组蛋白去乙酰化酶(HDACs)在肿瘤中起着至关重要的作用，但HDAC7在非小细胞肺癌（NSCLC）中的作用和机制尚不完全清楚。.方法:共纳入319例接受手术治疗的非小细胞肺癌(NSCLC)患者。通过免疫组化和Kaplan-Meier生存分析探讨HDAC7、FGF18 (fibroblast growth factor 18)表达与临床病理特征的关系。通过体内外细胞功能实验研究其对NSCLC细胞增殖和转移的影响。应用重组慢病毒介导的体内基因过表达或敲低、实时聚合酶链反应(PCR)、western blotting和免疫共沉淀等方法，阐明HDAC7促进NSCLC进展的潜在分子机制。.结果:HDAC7或FGF18表达升高与NSCLC患者预后不良、肿瘤淋巴结转移(TNM)分期及肿瘤分化呈正相关。HDAC7和FGF18同时高表达的NSCLC患者预后最差。HDAC7过表达通过上调FGF18促进NSCLC的增殖和转移。相反，过表达FGF18逆转了下调HDAC7介导的肿瘤生长和转移能力的减弱。从机制上看，我们的结果表明HDAC7与β-catenin相互作用导致β-catenin Lys49位点乙酰化水平下降，Ser45位点磷酸化水平下降。因此，hdac7介导的β-catenin翻译后修饰促进了核转移，并通过与TCF4结合激活了FGF18的表达。此外，去泛素酶USP10与HDAC7相互作用并稳定HDAC7。USP10的抑制显著加速了HDAC7的降解，削弱了NSCLC的生长和迁移。.结论:我们的研究结果揭示HDAC7通过USP10的稳定和激活β-catenin-FGF18通路促进NSCLC的进展。靶向这种新途径可能是NSCLC治疗进一步发展的一种有前途的策略。