DataSheet_8_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.

抗沉默因子1B组蛋白伴侣（anti-silencing function 1B histone chaperone，ASF1B）已被证实是肿瘤发生过程的重要调控因子，但其在肺腺癌（lung adenocarcinoma，LUAD）中的作用仍有待明确。本研究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）数据集后发现，除LAML外的所有受试癌种中均存在ASF1B的过表达。遗传、表观遗传、微卫星不稳定性（microsatellite instability，MSI）与肿瘤突变负荷（tumor mutational burden，TMB）分析显示，ASF1B的表达受单一或多种因素调控。Kaplan-Meier生存曲线分析表明，ASF1B表达上调与患者生存预后的关联具有癌种依赖性，可表现为良好或不良预后。本研究借助CIBERSORT算法评估肿瘤免疫微环境的细胞组成，对比肿瘤与正常组织样本后发现，ASF1B表达与免疫细胞浸润程度间存在显著的特异性关联。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存在关联。在肺腺癌细胞系中敲低ASF1B可抑制细胞增殖、干扰细胞周期分布并诱导细胞凋亡。与之相对，ASF1B过表达对肺腺癌细胞的恶性生物学特征无明显影响。在分子机制层面，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ε亚基3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）与二氢叶酸还原酶（dihydrofolate reductase，DHFR）的间接调控因子。综上，本研究数据表明ASF1B可作为肿瘤促发因子与潜在的癌症治疗靶点，同时为深入解析ASF1B在多种癌种中的关键作用提供了线索。