A Functional Genomic Approach Identifies FAL1 as an Oncogenic Long Noncoding RNA that Associates with BMI1 and Represses p21 Expression in Cancer

• Published in: Cancer cell Vol. 26; no. 3; pp. 344 - 357
• Main Authors: Hu, Xiaowen, Feng, Yi, Zhang, Dongmei, Zhao, Sihai D., Hu, Zhongyi, Greshock, Joel, Zhang, Youyou, Yang, Lu, Zhong, Xiaomin, Wang, Li-Ping, Jean, Stephanie, Li, Chunsheng, Huang, Qihong, Katsaros, Dionyssios, Montone, Kathleen T., Tanyi, Janos L., Lu, Yiling, Boyd, Jeff, Nathanson, Katherine L., Li, Hongzhe, Mills, Gordon B., Zhang, Lin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.09.2014
• Subjects: Animals; Cell Line, Tumor; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Genomics; Humans; Kaplan-Meier Estimate; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - metabolism; Neoplasms, Glandular and Epithelial - mortality; Neoplasms, Glandular and Epithelial - pathology; Oncogenes; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - mortality; Ovarian Neoplasms - pathology; Polycomb Repressive Complex 1 - metabolism; Polymorphism, Single Nucleotide; Protein Stability; RNA Interference; RNA, Long Noncoding - physiology; Transcriptome; Tumor Burden
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccr.2014.07.009

In a genome-wide survey on somatic copy-number alterations (SCNAs) of long noncoding RNA (lncRNA) in 2,394 tumor specimens from 12 cancer types, we found that about 21.8% of lncRNA genes were located in regions with focal SCNAs. By integrating bioinformatics analyses of lncRNA SCNAs and expression with functional screening assays, we identified an oncogene, focally amplified lncRNA on chromosome 1 (FAL1), whose copy number and expression are correlated with outcomes in ovarian cancer. FAL1 associates with the epigenetic repressor BMI1 and regulates its stability in order to modulate the transcription of a number of genes including CDKN1A. The oncogenic activity of FAL1 is partially attributable to its repression of p21. FAL1-specific siRNAs significantly inhibit tumor growth in vivo. [Display omitted] •Copy number of lncRNA genes is altered in human cancer with high frequency•FAL1 amplification and high expression correlate with poor outcome in cancer•FAL1 stabilizes BMI1 by RNA-protein interaction and represses p21 transcription•Repressing FAL1 expression by siRNA inhibits tumor growth in vivo Large-scale screening by Hu et al. reveals frequent SCNAs of lncRNAs in many cancers. One of these lncRNAs, FAL1, associates with poor outcomes in ovarian cancer patients and stabilizes BMI1 to promote tumor growth.