Song Congkuan, Lin Weichen, Meng Heng, Li Ning, Geng Qing
Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
Front Genet. 2022 Aug 22;13:862977. doi: 10.3389/fgene.2022.862977. eCollection 2022.
Histone deacetylases comprise a family of 18 genes, and classical HDACs are a promising class of novel anticancer drug targets. However, to date, no systematic study has been comprehensive to reveal the potential significance of these 18 genes in lung adenocarcinoma (LUAD). Here, we used a systematic bioinformatics approach to comprehensively describe the biological characteristics of the HDACs in LUAD. Unsupervised consensus clustering was performed to identify LUAD molecular subtypes. The ssGSEA, CIBERSORT, MCP counter, and ESTIMATE algorithms were used to depict the tumor microenvironment (TME) landscape. The Cox proportional hazards model and LASSO regression analyses were used to construct the HDAC scoring system for evaluating the prognosis of individual tumors. In this study, three distinct HDAC-mediated molecular subtypes were determined, which were also related to different clinical outcomes and biological pathways. HDACsCluster-C subtype had lowest PD-L1/PD-1/CTLA4 expression and immune score. The constructed HDAC scoring system (HDACsScore) could be used as an independent predictor to assess patient prognosis and effectively identify patients with different prognosis. High- and low-HDACsScore groups presented distinct genetic features, immune infiltration, and biological processes. The high-HDACsScore group was more likely to benefit from immunotherapy, as well as from the application of common chemotherapeutic agents (cyclopamine, docetaxel, doxorubicin, gemcitabine, paclitaxel, and pyrimethamine). Overall, HDAC family genes play important roles in LUAD, and the three LUAD subtypes and the HDAC scoring system identified in this study would help enhance our perception of LUAD prognostic differences and provide important insights into the efficacy of immunotherapy and chemotherapy.
组蛋白去乙酰化酶由18个基因组成的一个家族，经典的组蛋白去乙酰化酶是一类很有前景的新型抗癌药物靶点。然而，迄今为止，尚无系统研究全面揭示这18个基因在肺腺癌（LUAD）中的潜在意义。在此，我们采用系统的生物信息学方法全面描述LUAD中组蛋白去乙酰化酶的生物学特征。进行无监督一致性聚类以识别LUAD分子亚型。使用单样本基因集富集分析（ssGSEA）、CIBERSORT、MCP counter和ESTIMATE算法来描绘肿瘤微环境（TME）景观。采用Cox比例风险模型和LASSO回归分析构建用于评估个体肿瘤预后的组蛋白去乙酰化酶评分系统。在本研究中，确定了三种不同的组蛋白去乙酰化酶介导的分子亚型，它们也与不同的临床结局和生物学途径相关。组蛋白去乙酰化酶聚类-C亚型的程序性死亡配体1（PD-L1）/程序性死亡蛋白1（PD-1）/细胞毒性T淋巴细胞相关蛋白4（CTLA4）表达和免疫评分最低。构建的组蛋白去乙酰化酶评分系统（HDACsScore）可作为独立预测指标来评估患者预后，并有效识别不同预后的患者。高和低组蛋白去乙酰化酶评分组呈现出不同的基因特征、免疫浸润和生物学过程。高组蛋白去乙酰化酶评分组更有可能从免疫治疗以及常用化疗药物（环杷明、多西他赛、阿霉素、吉西他滨、紫杉醇和乙胺嘧啶）的应用中获益。总体而言，组蛋白去乙酰化酶家族基因在LUAD中发挥重要作用，本研究中确定的三种LUAD亚型和组蛋白去乙酰化酶评分系统将有助于增强我们对LUAD预后差异的认识，并为免疫治疗和化疗的疗效提供重要见解。
