Abstract
BackgroundElucidating mechanisms in oncogenes and epigenetic modifiers are needed to gain insights into the etiology and treatment of cancer, regulation of oncogene by chromatin modifiers at post-transcriptional level is critical and remains unclear. We have investigated the role of GINS4 in NSCLC.MethodsThe expression of chromatin modifier lymphoid-specific helicase (LSH) and GINS4 was assessed in tumor and normal tissue from 79 patients with NSCLC with clinical characteristics. HBE, A549, H358, and H522, PC9, 95C and 95D were cultured after overexpression or silencing of GIAT4RA. Cell proliferation assay, cell migration and invasion assays, plate colony formation assay, immunofluorescence assay, Operetta® high-content screening and analysis, Western blot analysis and Co-Immunoprecipitation (Co-IP) assay, RNA immunoprecipitation assay and tumor growth assay was used to address the potential interplay of between GINS4 and LSH, and the functional of GINS4.ResultsGINS4 is highly expressed in lung cancer cells and tissues, and GINS4 expression is not association with clinical risk factors, but linked with clinical stage and lymphatic metastasis status. Higher expression of GINS4 poorly linked with overall survival in lung adenocarcinomas. Furthermore, GINS4 promoted many characteristics of tumorigenesis including cell growth, clonal formation, migration and invasion, epithelial–mesenchymal transition, tumor sphere and tumor growth in vivo. Interestingly, our results demonstrated that LSH increases GINS4 expression through binding to 3’UTR region of GINS4 and stabilizing its mRNA levels. Finally, LSH overexpression rescues GINS4 knockdown-induced features.ConclusionsGINS4 facilitates lung cancer progression by promoting key characteristics of tumor potential, and LSH epigenetically interacts with and stabilizes GINS4 transcripts.
Highlights
Elucidating mechanisms in oncogenes and epigenetic modifiers are needed to gain insights into the etiology and treatment of cancer, regulation of oncogene by chromatin modifiers at post-transcriptional level is critical and remains unclear
Lung cancer is classified into small cell lung cancer and non-small cell lung cancer (NSCLC), including adenocarcinomas (ADC) and squamous cell carcinoma (SCC), which account for 80–85% of all lung cancer cases [1]
GINS4 is highly expressed in lung cancer tissues and is associated with the poor survival of patients with lung ADC We previously found that Lymphoidspecific helicase (LSH) upregulated GINS4 mRNA expression using RNA sequencing [36]
Summary
Elucidating mechanisms in oncogenes and epigenetic modifiers are needed to gain insights into the etiology and treatment of cancer, regulation of oncogene by chromatin modifiers at post-transcriptional level is critical and remains unclear. Epigenetic modifiers, including chromatin remodeling factors, play important roles in cancer development and progression [1, 3]. Studies performed on oncogenes and cancer epigenetic factors over the last decade have identified numerous epigenetic modifiers that are involved in the progression of various cancers [4,5,6,7,8], mechanisms underlying the interplay between epigenetic factors and oncogenes in lung cancer remain unclear. Our recent study indicated that lncRNA HOTAIR interacts and forms an intact complex with LSH to affect the expression of target genes [26]
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