Functional characterization and clinical significance of super-enhancers in lung adenocarcinoma
Functional characterization and clinical significance of super-enhancers in lung adenocarcinoma
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DOI：
10.1002/mc.23419
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发表时间：
2022-05-21
影响因子：
4.6
通讯作者：
Ma, Hongxia
中科院分区：
文献类型：
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作者：
Jiang, Xiangxiang;Qin, Na;Ma, Hongxia
超增强子（SE）是肿瘤发生中重要的转录调控因子，但其在肺腺癌（LUAD）中的功能特征和临床意义尚不清楚。通过使用两种LUAD细胞系和八种肺组织的H3 K27 ac ChIP-seq数据，我们检测了1045个癌症特异性SE和5032个正常特异性SE。与正常特异性SE相比，癌症特异性SE具有不同的调节机制，其中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 Proto-Oncogene，AP-1 Transcription Factor Subunit和Jun Proto-Oncogene，AP-1 Transcription Factor Subunit家族的转录因子调节。通过使用来自癌症基因组图谱的513个LUAD和57个邻近样本以及来自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，我们对SE的靶基因进行了差异表达分析，并定义了243个关键SE。关键SE的无监督聚类揭示了具有不同水平的基因组畸变的两种亚型（即，突变和拷贝数改变）和临床结果（无进展间隔：p = 0.030;无疾病间隔：p = 0.047）。此外，具有不良临床结果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，并且它们的靶点（PSMB 5和TOP 2A）在这些患者中也具有升高的表达水平。总之，我们的研究结果提供了一个全面的表征SE在LUAD，并强调其在LUAD治疗的临床意义。
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.