Systematic lncRNA mapping to genome-wide co-essential pathways uncovers cancer dependency on uncharacterized lncRNAs

Abstract

Quantification of gene dependency across hundreds of cell lines using genome-scale CRISPR screens have revealed co-essential pathways/modules and critical functions of uncharacterized genes. In contrast to protein-coding genes, robust CRISPR-based loss-of-function screens are lacking for long non-coding RNAs (lncRNAs), which are key regulators of many cellular process, leaving many essential lncRNAs unidentified and uninvestigated. Integrating copy-number, epigenetic, and transcriptomic data of >800 cancer cell lines with CRISPR-derived co-essential pathways, our method recapitulates known essential lncRNAs and predicts proliferation/growth dependency of 289 poorly characterized lncRNAs. Analyzing lncRNA dependencies across ten cancer types and their expression alteration by diverse growth-inhibitors across cell types, we prioritize 30 high-confidence pan-cancer proliferation/growth-regulating lncRNAs. Further evaluating two previously uncharacterized top proliferation suppressive lncRNAs (PSLR-1, PSLR-2) showed they are transcriptionally regulated by p53, induced by multiple cancer treatments, and significantly correlate to increased cancer patient survival. These lncRNAs modulate G2 cell cycle-regulating genes within the FOXM1 transcriptional network, inducing a G2 arrest and inhibiting proliferation and colony formation. Collectively, our results serve as a powerful resource for exploring lncRNA-mediated regulation of cellular fitness in cancer, circumventing current limitations in lncRNA research.

Cancer cells survival is dependent on the lincRNA JUNI

“…Second, low constitutive JNK activation may induce autophagy and exerts a protective activity (32,33). Sporadic references to JUNI as a cancerrelevant, poorly characterized lncRNA have been recently reported (34,35). How JUNI impacts tumorigenesis and consequently survival of cancer patients is a ground opened for research.…”