Dataset Information

Typical Enhancers, Super-Enhancers, and Cancers.

ABSTRACT: Non-coding segments of the human genome are enriched in cis-regulatory modules that constitute functional elements, such as transcriptional enhancers and Super-enhancers. A hallmark of cancer pathogenesis is the dramatic dysregulation of the "archetype" gene expression profiles of normal human cells. Genomic variations can promote such deficiencies when occurring across enhancers and Super-enhancers, since they affect their mechanistic principles, their functional capacity and specificity, and the epigenomic features of the chromatin microenvironment across which these regulatory elements reside. Here, we comprehensively describe: fundamental mechanisms of gene expression dysregulation in cancers that involve genomic abnormalities within enhancers' and Super-enhancers' (SEs) sequences, which alter the expression of oncogenic transcription factors (TFs); cutting-edge technologies applied for the analysis of variation-enriched hotspots of the cancer genome; and pharmacological approaches for the treatment of Super-enhancers' aberrant function. Finally, we provide an intratumor meta-analysis, which highlights that genomic variations in transcription-factor-driven tumors are accompanied overexpression of genes, a portion of which encodes for additional cancer-related transcription factors.

SUBMITTER: Koutsi MA

PROVIDER: S-EPMC9496678 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Typical Enhancers, Super-Enhancers, and Cancers.

Koutsi Marianna A MA Pouliou Marialena M Champezou Lydia L Vatsellas Giannis G Giannopoulou Angeliki-Ioanna AI Piperi Christina C Agelopoulos Marios M

Cancers 20220908 18

Non-coding segments of the human genome are enriched in <i>cis</i>-regulatory modules that constitute functional elements, such as transcriptional enhancers and Super-enhancers. A hallmark of cancer pathogenesis is the dramatic dysregulation of the "archetype" gene expression profiles of normal human cells. Genomic variations can promote such deficiencies when occurring across enhancers and Super-enhancers, since they affect their mechanistic principles, their functional capacity and specificity ...[more]

PMID: 36139535

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Project description:Background It 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. Methods Both 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. Results The 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. Conclusions In 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

Typical Enhancers, Super-Enhancers, and Cancers.

Publications

Typical Enhancers, Super-Enhancers, and Cancers.

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