Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
Mol Carcinog. 2022 Aug;61(8):776-786. doi: 10.1002/mc.23419. Epub 2022 May 21.
Super-enhancers (SEs) are important transcriptional regulators in tumorigenesis; however, the functional characterization and clinical significance of SEs in lung adenocarcinoma (LUAD) remain unclear. By using H3K27ac ChIP-seq data of two LUAD cell lines and eight lung tissues, we detected 1045 cancer-specific and 5032 normal-specific SEs. Compared to normal-specific SEs, cancer-specific SEs have different regulatory mechanisms where associated target genes were enriched in critical tumor-related pathways and tended to be regulated by transcription factors of Fos Proto-Oncogene, AP-1 Transcription Factor Subunit and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit families. By using expression data of 513 LUAD and 57 adjacent samples from The Cancer Genome Atlas and 80 tumor-normal paired LUAD samples from the Nanjing Lung Cancer Cohort study, we performed differential expression analysis of target genes for SEs and defined 243 crucial SEs. Unsupervised clustering of crucial SEs revealed two subtypes with different levels of genomic aberrations (i.e., mutation and copy number alteration) and clinical outcomes (progression-free interval: p = 0.030; disease-free interval: p = 0.047). In addition, patients with adverse clinical outcomes were more sensitive to three small molecule inhibitors (bortezomib, doxorubicin, and etoposide), and their targets (PSMB5 and TOP2A) also have elevated expression levels among these patients. Taken together, our findings provided a comprehensive characterization of SEs in LUAD and emphasized their clinical significance in LUAD therapy.
超级增强子（SEs）是肿瘤发生中的重要转录调控因子；然而，SEs 在肺腺癌（LUAD）中的功能特征和临床意义仍不清楚。我们使用了两个 LUAD 细胞系和 8 个肺组织的 H3K27ac ChIP-seq 数据，检测到了 1045 个肿瘤特异性和 5032 个正常特异性 SEs。与正常特异性 SEs 相比，肿瘤特异性 SEs 具有不同的调控机制，其相关靶基因富集在关键的肿瘤相关通路中，并且倾向于受 Fos 原癌基因、AP-1 转录因子亚基和 Jun 原癌基因、AP-1 转录因子亚基家族的转录因子调控。我们使用了来自癌症基因组图谱的 513 个 LUAD 和 57 个相邻样本以及南京肺癌队列研究的 80 个肿瘤-正常配对 LUAD 样本的表达数据，对 SEs 的靶基因进行了差异表达分析，并定义了 243 个关键 SEs。对关键 SEs 的无监督聚类揭示了两种具有不同基因组异常（即突变和拷贝数改变）和临床结局（无进展间隔：p=0.030；无病间隔：p=0.047）水平的亚型。此外，具有不良临床结局的患者对三种小分子抑制剂（硼替佐米、多柔比星和依托泊苷）更敏感，并且这些患者的靶基因（PSMB5 和 TOP2A）的表达水平也升高。总之，我们的研究结果提供了 LUAD 中 SEs 的全面特征，并强调了它们在 LUAD 治疗中的临床意义。
