Abstract
Long noncoding RNAs (lncRNAs) are deeply involved in cancer development. We previously reported that DLEU1 (deleted in lymphocytic leukemia 1) is one of the lncRNAs overexpressed in oral squamous cell carcinoma (OSCC) cells, where it exhibits oncogenic activity. In the present study, we further clarified the molecular function of DLEU1 in the pathogenesis of OSCC. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis revealed that DLEU1 knockdown induced significant changes in the levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3K27 acetylation (H3K27ac) in OSCC cells. Notably, DLEU1 knockdown suppressed levels of H3K4me3/ H3K27ac and expression of a number of interferon-stimulated genes (ISGs), including IFIT1, IFI6 and OAS1, while ectopic DLEU1 expression activated these genes. Western blot analysis and reporter assays suggested that DLEU1 upregulates ISGs through activation of JAK-STAT signaling in OSCC cells. Moreover, IFITM1, one of the ISGs induced by DLUE1, was frequently overexpressed in primary OSCC tumors, and its knockdown inhibited OSCC cell proliferation, migration and invasion. These findings suggest that DLEU1 exerts its oncogenic effects, at least in part, through activation of a series ISGs in OSCC cells.
Highlights
Long noncoding RNAs are deeply involved in cancer development
After confirming that transfecting oral squamous cell carcinoma (OSCC) cell lines (HSC3, KON and Ca9-22) with siRNA targeting deleted in lymphocytic leukemia 1 (DLEU1) depleted its expression (Supplementary Fig. S1b), we performed chromatin immunoprecipitation-sequencing (ChIP-seq) to assess genomewide histone H3 lysine 4 trimethylation (H3K4me3) and H3K27 acetylation (H3K27ac) in HSC3 cells transfected with siDLEU1-2 or a control siRNA (Fig. 1a)
Metagene plot analysis of the transcription start sites (TSSs) of all RefSeq genes revealed that levels of H3K4me[3] were moderately elevated while those of H3K27ac were significantly decreased in HSC3 cells, which suggests a number of genes are transcriptionally downregulated by DLEU1 depletion (Fig. 1b)
Summary
Long noncoding RNAs (lncRNAs) are deeply involved in cancer development. We previously reported that DLEU1 (deleted in lymphocytic leukemia 1) is one of the lncRNAs overexpressed in oral squamous cell carcinoma (OSCC) cells, where it exhibits oncogenic activity. IFITM1, one of the ISGs induced by DLUE1, was frequently overexpressed in primary OSCC tumors, and its knockdown inhibited OSCC cell proliferation, migration and invasion These findings suggest that DLEU1 exerts its oncogenic effects, at least in part, through activation of a series ISGs in OSCC cells. The treatment modalities used for oral cancers include surgery, chemotherapy, radiation therapy and immunotherapy, applied alone or in some combination, depending on the location and/or stage of the disease These treatments can be effective, they are often unsatisfactory with advanced or recurrent disease, and the 5-year survival rate among oral cancer patients remains approximately 50%. Targeted therapies, such as cetuximab (monoclonal antibody for EGFR), are reportedly effective against inoperable and chemotherapy-resistant oral c ancers[2,3]. Interferon alpha/beta signaling Interferon Signaling Cytokine Signaling in Immune system Signaling by GPCR Immune System GPCR downstream signaling Metabolism of RNA OAS antiviral response Antiviral mechanism by ISGs Interferon gamma signaling
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