Colon Cancer-Upregulated Long Non-Coding RNA lincDUSP Regulates Cell Cycle Genes and Potentiates Resistance to Apoptosis

• Published in: Scientific reports Vol. 8; no. 1; pp. 7324 - 12
• Main Authors: Forrest, Megan E., Saiakhova, Alina, Beard, Lydia, Buchner, David A., Scacheri, Peter C., LaFramboise, Thomas, Markowitz, Sanford, Khalil, Ahmad M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.05.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 13/31; 13/89; 14/1; 38/71; 38/91; 45/15; 631/208/200; 631/67/68; 82/80; 96/63; Apoptosis; Cell cycle; Cell proliferation; Chromatin; Colon cancer; Colorectal cancer; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; Genomes; Humanities and Social Sciences; multidisciplinary; Non-coding RNA; Science; Science (multidisciplinary); Tumor cell lines; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-25530-5

Long non-coding RNAs (lncRNAs) are frequently dysregulated in many human cancers. We sought to identify candidate oncogenic lncRNAs in human colon tumors by utilizing RNA sequencing data from 22 colon tumors and 22 adjacent normal colon samples from The Cancer Genome Atlas (TCGA). The analysis led to the identification of ~200 differentially expressed lncRNAs. Validation in an independent cohort of normal colon and patient-derived colon cancer cell lines identified a novel lncRNA, lincDUSP, as a potential candidate oncogene. Knockdown of lincDUSP in patient-derived colon tumor cell lines resulted in significantly decreased cell proliferation and clonogenic potential, and increased susceptibility to apoptosis. The knockdown of lincDUSP affects the expression of ~800 genes, and NCI pathway analysis showed enrichment of DNA damage response and cell cycle control pathways. Further, identification of lincDUSP chromatin occupancy sites by ChIRP-Seq demonstrated association with genes involved in the replication-associated DNA damage response and cell cycle control. Consistent with these findings, lincDUSP knockdown in colon tumor cell lines increased both the accumulation of cells in early S-phase and γH2AX foci formation, indicating increased DNA damage response induction. Taken together, these results demonstrate a key role of lincDUSP in the regulation of important pathways in colon cancer.