Mol Oncol 2020 May 27. Epub 2020 May 27.
The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, 515041, China.
Long non-coding RNAs (lncRNAs) have important regulatory roles in cancer biology. Although some lncRNAs have well-characterized functions, the vast majority of this class of molecules remains functionally uncharacterized. To systematically pinpoint functional lncRNAs, a computational approach was proposed for identification of lncRNA-mediated competing endogenous RNAs (ceRNAs) through combining global and local regulatory direction consistency of expression. Using esophageal squamous cell carcinoma (ESCC) as model, we further identified many known and novel functional lncRNAs acting as ceRNAs (ce-lncRNAs). We found that most of them significantly regulated the expression of cancer-related hallmark genes. These ce-lncRNAs were significantly regulated by enhancers, especially super-enhancers (SEs). Landscape analyses for lncRNAs further identified SE-associated functional ce-lncRNAs in ESCC, such as HOTAIR, XIST, SNHG5 and LINC00094. THZ1, a specific CDK7 inhibitor, can result in global transcriptional downregulation of SE-associated ce-lncRNAs. We further demonstrate that a SE-associated ce-lncRNA, LINC00094 can be activated by transcription factors TCF3 and KLF5 through binding to super-enhancer regions and promoted ESCC cancer cell growth. THZ1 downregulated expression of LINC00094 through inhibiting TCF3 and KLF5. Our data demonstrated the important roles of SE-associated ce-lncRNAs in ESCC oncogenesis and might serve as targets for ESCC diagnosis and therapy.