Pan-Cancer Analysis of lncRNA regulation supports their targeting of cancer genes in each tumor context

Long noncoding RNAs (lncRNAs) are commonly dysregulated in tumors, but only a handful are known to play pathophysiological roles in cancer. A team led by researchers at Baylor College of Medicine inferred lncRNAs that dysregulate cancer pathways, oncogenes, and tumor suppressors (cancer genes) by modeling their effects on the activity of transcription factors, RNA-binding proteins, and microRNAs in 5,185 TCGA tumors and 1,019 ENCODE assays. Thier predictions included hundreds of candidate onco- and tumor-suppressor lncRNAs (cancer lncRNAs) whose somatic alterations account for the dysregulation of dozens of cancer genes and pathways in each of 14 tumor contexts. To demonstrate proof of concept, the research team showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor) and TUG1 and WT1-AS (inferred onco-lncRNAs) dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells. This analysis indicates that, although most lncRNAs are dysregulated in a tumor-specific manner, some, including OIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergistically dysregulate cancer pathways in multiple tumor contexts.

lncNETs in Cancer

(A) LongHorn predicts lncRNA interactions using four models for lncRNA regulation. These include lncRNA decoys that bind and inhibit the activity of TFs, RBPs, and miRNAs (effectors), thus affecting their availability to regulate their targets; co-factors and guides that bind proximal promoters of protein-coding genes (PCGs) and alter their regulation by TFs; and switches that alter the activity of TFs and RBPs across multiple targets.

(B) The models consider lncRNAs to be modulators of effector activity (i.e., the role of lncRNAs is to alter regulation by effectors). For example, OIP5-AS1 was predicted to modulate effectors that target the preotein coding genes (PCGs) PIK3R1, TCF4, ZEB1, FOXA1, FOXP1, and PTEN in TCGA breast-invasive carcinomas tumors.

(C) Activity modulation by OIP5-AS1 was observed when comparing distance correlation between effectors and targets in samples with low and high OIP5-AS1 abundance. OIP5-AS1 was upregulated in luminal tumors, where it was predicted to enhance IRF4, ETS1, EOMES, and CREB5 activity, leading to dysregulation of their common PCG targets PIK3R1, TCF4, and ZEB1.

(D) OIP5-AS1 was downregulated in basal-like tumors, where it was predicted to inhibit the activity of regulators, including TIA1, MAX, and miR-769-3p, leading to the dysregulation of their targets FOXA1, FOXP1, and PTEN; the top three effectors are shown for each target. ^∗p < 5E−2, ^∗∗p < 1E−2, ^∗∗∗p < 1E−3, and ^∗∗∗∗p < 1E−4, as estimated by bootstrapping.