Long Non-Coding RNA-Based Functional Prediction Reveals Novel Targets in Notch-Upregulated Ovarian Cancer

SIMPLE SUMMARY: The study contributes to our understanding of the role of lncRNAs in the regulation of Notch signaling and their target genes in ovarian cancer. These lncRNAs were identified with in silico analyses using The Cancer Genome Atlas and the results were validated using our transcriptome data from the in vitro NOTCH1/3 silencing experiments and the qRT-PCR analysis, using tissue samples from patients with ovarian tumors. Finally, to improve our understanding of the complexity of Notch signaling, we identified master transcriptional factors which might orchestrate the upregulation of Notch-related lncRNAs and coding-genes in ovarian cancer. ABSTRACT: Notch signaling is a druggable target in high-grade serous ovarian cancers; however, its complexity is not clearly understood. Recent revelations of the biological roles of lncRNAs have led to an increased interest in the oncogenic action of lncRNAs in various cancers. In this study, we performed in silico analyses using The Cancer Genome Atlas data to discover novel Notch-related lncRNAs and validated our transcriptome data via NOTCH1/3 silencing in serous ovarian cancer cells. The expression of novel Notch-related lncRNAs was down-regulated by a Notch inhibitor and was upregulated in high-grade serous ovarian cancers, compared to benign or borderline ovarian tumors. Functionally, Notch-related lncRNAs were tightly linked to Notch-related changes in diverse gene expressions. Notably, genes related to DNA repair and spermatogenesis showed specific correlations with Notch-related lncRNAs. Master transcription factors, including EGR1, CTCF, GABPα, and E2F4 might orchestrate the upregulation of Notch-related lncRNAs, along with the associated genes. The discovery of Notch-related lncRNAs significantly contributes to our understanding of the complex crosstalk of Notch signaling with other oncogenic pathways at the transcriptional level.