ArticleTranslational cancer research2020
Super-enhancers modulate interleukin-6 expression and function in cancers.
Article in Translational cancer research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed, 5 citations in OpenAlex.
- Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines.Cell reports · 2024Article
- Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin.International journal of molecular sciences · 2024Review
- The Emerging Role of Super-enhancers as Therapeutic Targets in The Digestive System Tumors.International journal of biological sciences · 2023Review
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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