Therapeutic Targeting of Long Non-Coding RNAs in Cancer

Abstract

Long non-coding RNAs (lncRNAs) represent a significant population of the human transcriptome. Many lncRNAs exhibit cell- and/or tissue/tumor-specific expression, making them excellent candidates for therapeutic applications. In this review we discuss examples of lncRNAs that demonstrate the diversity of their function in various cancer types. We also discuss recent advances in nucleic acid drug development with a focus on oligonucleotide-based therapies as a novel approach to inhibit tumor progression. The increased success rates of nucleic acid therapeutics provide an outstanding opportunity to explore lncRNAs as viable therapeutic targets to combat various aspects of cancer progression.

Figure 1. Proposed molecular functions of mammalian lncRNAs

The schematic depicts examples of proposed lncRNA (red) molecular functions and their location in corresponding cellular compartments. a) ANRIL represses gene transcription of the INK4 locus in cis by binding to polycomb repressive complex 1 (PRC1, green). b) CCAT2 activates expression of WNT target genes including MYC, possibly by directly interacting with the transcription factor TCF7L2 (light blue). c) H19 is a precursor for miR-675. The lncRNA is processed to pre-miR-675, which is exported into the cytoplasm and further processed to miR-675. The mature miRNA assembles with RNA-induced silencing complex (RISC, dark green). The tumor suppressor RB is one of the targets of miR-675. d) MALAT1 associates with SR splicing factors (orange) and is located in nuclear speckles. e) H19 also acts as a sponge for many different miRNAs, including members of the miR-200 family. f) GAS5 functions as a decoy for glucocorticoid receptor (GR, purple), preventing GR-dependent gene activation.

Key Figure, Figure 2

Therapeutic targeting of human lncRNAs The schematic summarizes different approaches to target lncRNAs in the nucleus and cytoplasm. a) Transcriptional inhibition can be attained through classical CRISPR/Cas9 to delete regions of interest in lncRNA loci. Alternatively, dead-Cas9 fused to a repressor complex can inhibit transcription of lncRNA genes. b) Transcriptional upregulation of tumor suppressors can be attained through knockdown of the corresponding Natural Antisense Transcripts (NATs). NATs can be targeted post-transcriptionally using ASOs. c) ASOs can also be used to post-transcriptionally knockdown lncRNAs that are overexpressed in cancers. d) Post-transcriptional silencing can also be achieved by siRNAs targeting lncRNAs. SiRNAs stimulate Dicer activity in the cytoplasm and recruit RISC complex (RNA Induced Silencing Complex) to post-transcriptionaly degrade target RNAs e) Steric inhibition of lncRNA-protein interactions can be achieved using small molecules, morpholinos, or uniformly-modified ASOs that cannot stimulate an RNA degradation pathway.