Functional characterization and clinical significance of super‐enhancers in lung adenocarcinoma

作者：Xiangxiang Jiang, Na Qin, Tingting Hua, Xiaoxia Wei, Yuancheng Li, Congcong Chen, Linnan Gong, Su Liu, Cheng Wang, Rong Yin, Yue Jiang, Juncheng Dai, Lin Xu, Hongbing Shen, Hongxia Ma · 发表于：Molecular Carcinogenesis · 年份：2022 · DOI：10.1002/mc.23419 · 被引用次数：7 · 研究领域：Genomics and Chromatin Dynamics、RNA Research and Splicing、RNA modifications and cancer

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 comprehen...