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Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers.

ABSTRACT: Whole-genome analysis approaches are identifying recurrent cancer-associated somatic alterations in noncoding DNA regions. We combined somatic copy number analysis of 12 tumor types with tissue-specific epigenetic profiling to identify significant regions of focal amplification harboring super-enhancers. Copy number gains of noncoding regions harboring super-enhancers near KLF5, USP12, PARD6B and MYC are associated with overexpression of these cancer-related genes. We show that two distinct focal amplifications of super-enhancers 3' to MYC in lung adenocarcinoma (MYC-LASE) and endometrial carcinoma (MYC-ECSE) are physically associated with the MYC promoter and correlate with MYC overexpression. CRISPR/Cas9-mediated repression or deletion of a constituent enhancer within the MYC-LASE region led to significant reductions in the expression of MYC and its target genes and to the impairment of anchorage-independent and clonogenic growth, consistent with an oncogenic function. Our results suggest that genomic amplification of super-enhancers represents a common mechanism to activate cancer driver genes in multiple cancer types.

SUBMITTER: Zhang X

PROVIDER: S-EPMC4857881 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers.

Zhang Xiaoyang X Choi Peter S PS Francis Joshua M JM Imielinski Marcin M Watanabe Hideo H Cherniack Andrew D AD Meyerson Matthew M

Nature genetics 20151214 2

Whole-genome analysis approaches are identifying recurrent cancer-associated somatic alterations in noncoding DNA regions. We combined somatic copy number analysis of 12 tumor types with tissue-specific epigenetic profiling to identify significant regions of focal amplification harboring super-enhancers. Copy number gains of noncoding regions harboring super-enhancers near KLF5, USP12, PARD6B and MYC are associated with overexpression of these cancer-related genes. We show that two distinct foca ...[more]

PMID: 26656844

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Project description:BackgroundIt is widely accepted that inflammatory cytokine, interleukin 6 (IL-6), was not only elevated in cancer but also important in carcinogenesis. But how did IL-6 be produced in tumor microenvironment remains to be addressed.MethodsBoth bioinformatics tools and quantitative real time polymerase chain reaction (RT-PCR) were used to examine the expression of IL-6 in cancer cells. To map super-enhancers of IL-6, sgRNAs were constructed. Stable knockout cells were established and subsequently used for cell proliferation and colony formation assay. The correlation between mapped super-enhancers and IL-6 expression was studied by ATAC-seq analysis.ResultsThe expression of IL-6 was high in multiple cancers, including pancreatic cancer (PAAD). The elevated expression of IL-6 in PAAD was further confirmed by transcriptional data and in a panel of pancreatic cancer cell lines (one immortal HPDE6-C7 cell line and four PDAC cell lines: BxPC-3, PANC-1, AsPC-1 and CFPAC-1). When treated with JQ-1 and I-BET-762, two inhibitors of super-enhancers, the expression of IL-6 in multiple cancer cells including CFPAC-1, HeLa and SUM-159 cells was significantly reduced. By analyzing the H3K27Ac profiling, BRD4 binding, Med1 binding and DNA conservation in CFPAC-1, HeLa and SUM-159 cells, we identified a potential super-enhancer (IL6-SE) that might be important for IL-6 expression in cancer. The super-enhancer (IL6-SE) can be further divided into two elements (IL6-SEa and IL6-SEb). Genetic deletion of IL6-SEa in cancer cells greatly reduces the expression of IL-6. IL6-SEa deficient cells also showed low proliferation and colony formation ability. In patients, the epigenetic activation (ATAC signal) of IL6-SEa is correlated with the expression of IL-6.ConclusionsIn summary, we not only provide convincing experimental evidence to demonstrate that IL-6 expression in cancer is dependent on super-enhancers but also identified IL6-SEa as a critical DNA regulatory element. Our findings provide new insights to understand the epigenetic regulation of IL-6 expression in cancers.

Dataset Information

Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers.

Publications

Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers.

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