Abstract
FAL1 is an oncogenic lncRNA that promotes cancer cell growth in part via repression of p21.
Major finding: FAL1 is an oncogenic lncRNA that promotes cancer cell growth in part via repression of p21.
Mechanism: FAL1 regulates the transcription of genes including CDKN1A via stabilization of BMI1.
Impact: FAL1 may be a marker of poor prognosis and a potential therapeutic target in ovarian cancer.
A large percentage of somatic copy-number alterations (SCNA) in cancer cells occur in regions lacking protein-coding genes, adding to the challenge of identifying driver SCNAs that directly promote tumorigenesis. Long noncoding RNAs (lncRNA) are aberrantly expressed in many cancers and have been implicated as both oncogenes and tumor suppressors; however, whether recurrent genomic alterations in lncRNAs contribute to tumor growth remains unclear. Hu and colleagues characterized the genome-wide SCNA profile of lncRNAs across 12 cancer types and found that lncRNA genes exhibited high-frequency and cancer type–specific copy-number gains and losses. Functional screening of lncRNAs that demonstrated focal copy-number gain and RNA expression in cancer cell lines identified focally amplified lncRNA on chromosome 1 (FAL1) as a candidate oncogenic lncRNA. Depletion of FAL1 decreased the clonogenicity of cancer cell lines and impaired xenograft tumor growth, whereas FAL1 overexpression enhanced transformation. The oncogenic activity of FAL1 was mediated in part by its interaction with BMI1, a component of the chromatin-modifying Polycomb repressive complex 1, which resulted in increased stabilization of BMI1 protein and transcriptional repression of genes involved in processes such as cell proliferation and apoptosis. In particular, repression of cyclin-dependent kinase inhibitor 1A (CDKN1A, which encodes p21) was required for the protumorigenic functions of FAL1; knockdown of FAL1 stimulated cell-cycle arrest and senescence, which were both rescued by concomitant p21 depletion. Intriguingly, amplification and RNA expression of FAL1 were increased in late-stage ovarian tumors as compared with early-stage tumors and were associated with reduced survival in patients with late-stage ovarian cancer. Furthermore, siRNA-mediated inhibition of FAL1 diminished tumor growth in an orthotopic mouse model of late-stage ovarian cancer. These results demonstrate the utility of this integrated approach to identify oncogenic lncRNAs and suggest that FAL1 may represent a prognostic biomarker and therapeutic target in ovarian cancer.
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