Long Non-coding RNAs and their Role in Metastasis

Mode of action of lncNKILA, Tre lncRNA, HOTAIR, MALAT1, GClncRNA, BCAR4 and lncRNA-ATP. (A) NKILA acts as a negative regulator of NFĸB signaling. IĸB, inhibitor of ĸB; NFĸB, nuclear factor ĸ; NKILA, NFĸB-activating lncRNA; p50 and p65, subunits of NFĸB. Blue circles indicate polyubiquitinylation. (B) Tre lncRNA inhibits translation of pro-metastatic mRNAs via RNP formation by a poorly resolved mode of action. eIF-4G1, translation initiation factor 4G1; FXR1, FXR3, fragile X mental retardation syndrome-related proteins 1, 3; hnRNPK, heterogeneous ribonucleoprotein complex K; SF3B3, splicing factor 3B subunit 3; treRNA, translational regulatory RNA; treRNA RNP, tre RNA ribonucleoprotein complex. (C) HOTAIR represses gene expression by recruitment of PRC2 and LSD1 by increasing the repression code H3K27me3 and decreasing the activation code H3K4me3. DZIP3, DAZ interacting protein 3 (E3 ubiquitin-protein ligase); HOTAIR, HOX antisense intergenic RNA; H3K4me3, histone 3 trimethylated lysine 4; H3K27me3, histone 3 trimethylated lysine 27; LSD1, lysine-specific demethylase 1; PRC2, polycomb repressive complex 2. Blue circles indicate polyubiquitinylation. (D) MALAT1 relieves gene repression in polycomb bodies by replacement of TUG1 lncRNA and recruitment of co-activators in Interchromatin granules thus promoting G₁/S transition. CoA, co-activator; CoR, co-repressor; CH3, methyl group; E2F, transcription factor 2F; MALAT1, metastasis-associated lung adenocarcinoma transcript; Pc2, polycomb 2; Pc2-CH3, methylated Pc2; SUMO, sumoylated; lnc RNA TUG1, lnc RNA taurine-upregulated gene 1. Red/green arrow: inhibition/activation of transcription; red circles indicate sumoylation. (E) GClncRNA recruits histone modifiers such as WDR5 and KAT2A for transactivation of transcription of selected genes. GC lncRNA, Gastric cancer lncRNA; KAT2A, lysine acetyltransferase 2A; WDR5, WD repeat containing protein 5; SOD2, superoxide dismutase 2. Green arrow, indicates activation of transcription. (F) BCAR4 mediates activation of phospho-GLI-2 dependent target genes. BCAR4, Breast cancer anti-estrogen resistance; CCL21, chemokine (C-C motif) ligand 21; CCR7, CC-chemokine receptor 7; GLI2, glioma-associated oncogene family zinc finger 2; p, phosphorylated; PNUTS, putative protein phosphatase 1 nuclear; Pol II, polymerase II; Pp1, phosphatase 1; p300, E1A binding protein 300; SNIP1, smad nuclear interacting protein 1. Black arrows indicate phosphorylation of GLI2 by CCR7/CCL21 interaction; green arrows indicate activation of transcription. (G) lncRNA – ATP mimics the prometastatic role of TGFβ biy inducing miR200 family members and promotes IL11 signaling. EMT, Epithelial mesenchymal transition; IL11, interleukin 11; lnc RNA – ATP, lncRNA activated by TGFβ; STAT3, signal transducer and activator of transcription 3; TGFβ, transforming growth factor β; blue circled P, phosphorylation.