DataSheet_1_ASF1B Promotes Oncogenesis in Lung Adenocarcinoma and Other Cancer Types.pdf

Anti-silencing function 1B histone chaperone (ASF1B) is known to be an important modulator of oncogenic processes, yet its role in lung adenocarcinoma (LUAD) remains to be defined. In this study, an integrated assessment of The Cancer Genome Atlas (TCGA) and genotype-tissue expression (GTEx) datasets revealed the overexpression of ASF1B in all analyzed cancer types other than LAML. Genetic, epigenetic, microsatellite instability (MSI), and tumor mutational burden (TMB) analysis showed that ASF1B was regulated by single or multiple factors. Kaplan-Meier survival curves suggested that elevated ASF1B expression was associated with better or worse survival in a cancer type-dependent manner. The CIBERSORT algorithm was used to evaluate immune microenvironment composition, and distinct correlations between ASF1B expression and immune cell infiltration were evident when comparing tumor and normal tissue samples. Gene set enrichment analysis (GSEA) indicated that ASF1B was associated with proliferation- and immunity-related pathways. Knocking down ASF1B impaired the proliferation, affected cell cycle distribution, and induced cell apoptosis in LUAD cell lines. In contrast, ASF1B overexpression had no impact on the malignant characteristics of LUAD cells. At the mechanistic level, ASF1B served as an indirect regulator of DNA Polymerase Epsilon 3, Accessory Subunit (POLE3), CDC28 protein kinase regulatory subunit 1(CKS1B), Dihydrofolate reductase (DHFR), as established through proteomic profiling and Immunoprecipitation-Mass Spectrometry (IP-MS) analyses. Overall, these data suggested that ASF1B serves as a tumor promoter and potential target for cancer therapy and provided us with clues to better understand the importance of ASF1B in many types of cancer.

抗沉默功能1B组蛋白伴侣（Anti-silencing function 1B histone chaperone，ASF1B）是致癌过程的关键调控因子，但其在肺腺癌（lung adenocarcinoma，LUAD）中的具体作用仍有待阐明。本研究通过整合分析癌症基因组图谱（The Cancer Genome Atlas，TCGA）与基因型-组织表达（genotype-tissue expression，GTEx）数据集，发现ASF1B在除LAML外的所有分析癌种中均呈高表达。遗传、表观遗传、微卫星不稳定性（microsatellite instability，MSI）及肿瘤突变负荷（tumor mutational burden，TMB）分析显示，ASF1B的表达受到单一或多种因素的调控。卡普兰-迈耶生存曲线（Kaplan-Meier survival curves）分析表明，ASF1B高表达与患者生存的关联存在癌种依赖性，既可提示更佳的预后，也可提示更差的预后。本研究采用CIBERSORT算法评估肿瘤免疫微环境组成，对比肿瘤与正常组织样本可见，ASF1B表达与免疫细胞浸润的相关性存在显著差异。基因集富集分析（Gene set enrichment analysis，GSEA）结果显示，ASF1B与增殖及免疫相关通路密切相关。在LUAD细胞系中敲低ASF1B可抑制细胞增殖、影响细胞周期分布并诱导细胞凋亡；反之，过表达ASF1B则对LUAD细胞的恶性表型无显著影响。在机制层面，通过蛋白质组学分析与免疫沉淀-质谱联用（Immunoprecipitation-Mass Spectrometry，IP-MS）实验证实，ASF1B可作为DNA聚合酶ε3辅助亚基（DNA Polymerase Epsilon 3, Accessory Subunit，POLE3）、CDC28蛋白激酶调节亚基1（CDC28 protein kinase regulatory subunit 1，CKS1B）及二氢叶酸还原酶（Dihydrofolate reductase，DHFR）的间接调控因子。综上，本研究结果表明ASF1B可作为肿瘤促癌因子及癌症治疗的潜在靶点，同时为深入理解ASF1B在多种癌症中的重要作用提供了线索。