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Review
. 2018 Mar 31;3(3):108-117.
doi: 10.1016/j.ncrna.2018.03.001. eCollection 2018 Sep.

Exploring the mechanisms behind long noncoding RNAs and cancer

Maggie M Balas  1   2   3 , Aaron M Johnson  1   2   3
Affiliations
Review

Exploring the mechanisms behind long noncoding RNAs and cancer

Maggie M Balas et al. Noncoding RNA Res. .

Abstract

Over the past decade, long noncoding RNAs (lncRNAs) have been identified as significant players in gene regulation. They are often differentially expressed and widely-associated with a majority of cancer types. The aberrant expression of these transcripts has been linked to tumorigenesis, metastasis, cancer stage progression and patient survival. Despite their apparent link to cancer, it has been challenging to gain a mechanistic understanding of how they contribute to cancer, partially due the difficulty in discriminating functional RNAs from other noncoding transcription events. However, there are several well-studied lncRNAs where specific mechanisms have been more clearly defined, leading to new discoveries into how these RNAs function. One major observation that has come to light is the context-dependence of lncRNA mechanisms, where they often have unique function in specific cell types and environment. Here, we review the molecular mechanisms of lncRNAs with a focus on cancer pathways, illustrating a few informative examples. Together, this type of detailed insight will lead to a greater understanding of the potential for the application of lncRNAs as targets of cancer therapies and diagnostics.

Keywords: Cancer; Chromatin; HOTAIR; MEG3; TUG1; lncRNA.

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Figures

Fig. 1
Fig. 1
LncRNA classification based on genomic location. A) Intergenic lncRNAs are located between protein-coding genes. B) Bidirectional lncRNAs are transcribed from the same promoter as a protein-coding gene, but in the opposite direction. C) Antisense lncRNAs originate from the antisense RNA strand of a protein-coding gene. D) Sense-overlapping lncRNAs overlap with one or more introns and/or exons of a protein-coding gene in the sense RNA strand direction.
Fig. 2
Fig. 2
General mechanisms for lncRNA classification. A) lncRNAs can act as guides to target chromatin-modifying complexes to specific genomic locations for the regulation of gene expression. B) lncRNAs can act as dynamic scaffolds for cofactors to transiently assemble together. C) lncRNAs can bind to microRNAs or transcription factors as decoys to sequester them away from their targets, affecting transcription and translation.
Fig. 3
Fig. 3
LncRNAs associated with various cancer types.
Fig. 4
Fig. 4
Models of HOTAIR molecular mechanism in cancer. A) HOTAIR is transcribed from the HOXC locus on chromosome 12, scaffolds PRC2 and LSD1 chromatin-modifying complexes and targets them in trans to silence the HOXD locus on chromosome 2 through methylation of H3K27 and demethylation of H3K4 respectively. B) Model of c-Myc–mediated transcriptional activation in breast cancer, where the oncoprotein HBXIP acts as a co-activator by directly interacting with transcription factor c-Myc. HOTAIR scaffolds HBXIP and LSD1 to form a complex of c-Myc/HBXIP/HOTAIR/LSD1, which activates transcription of c-Myc target genes. C) Model for HOTAIR-PRC2 recruitment to specific genomic loci via RNA-RNA matchmaking, where hnRNP A2/B1 promotes HOTAIR binding to nascent transcripts of targets genes, resulting in PRC2-mediated transcriptional repression. D) In esophageal and epithelial cancers HOTAIR sequesters miR148-a, causing upregulation of Snail2 which results in increased cell invasion and metastasis. E) miR-141 can bind HOTAIR targeting it to AGO2, forming the Risc complex and subsequent HOTAIR degradation. F) In renal carcinoma, HOTAIR can bind to HuR, recruiting it to AGO2/let7, resulting in HOTAIR degradation. G) HOTAIR can bind E3 ubiquitin ligases Mex3b and Dzip3 and their target substrates Snurportin-1 and Ataxin-1 respectively, scaffolding them together and enhancing target substrate ubiquitination followed by protein degradation. H) In prostate cancer, HOTAIR can bind and stabilize the androgen receptor (AR), thereby blocking MDM2 association with AR and inhibiting ubiquitination and protein degradation of AR.
Fig. 5
Fig. 5
LncRNA TUG1 models for molecular mechanism. A) TUG1 can be induced by p53, Notch1 and SP1. TUG1 can bind to PRC2 and YY1 to repress transcription. TUG1 is upregulated or downregulated in multiple cancer types where it affects target gene expression contributing to cancer phenotypes. B) In glioma stem cells, TUG1 suppresses miR-145 thereby alleviating the repression of SOX2 and MYC. C) In bladder cancer, TUG1 binding to miR-145 targets it to the Risc complex resulting in ZEB2 transcription.
Fig. 6
Fig. 6
LncRNA MEG3 models of mechanism. A) MEG3 is expressed in normal tissue and significantly downregulated in many cancers, where hypermethylation of the MEG3 promoter inhibits normal activation by cAMP. B) MEG3 interacts with PRC2 and JARID2 to direct them to specific target promoters, via triplex formation with GA-rich DNA sequences, resulting in H3K27me3 and transcriptional repression. In lung cancer, MEG3-PRC2 represses TGF-β associated genes CDH1 and microRNA-200 family genes resulting in enhanced EMT. In colon and osteosarcoma carcinoma, MEG3 represses MDM2 which inhibits p53 activation. C) In hepatocellular cancer, MEG3 can bind to p53 to regulate p53 target gene expression, such as GDPH15. Upregulation of GDPH15 inhibits proliferation of cancer cells and tumor growth. D) Overexpression of MEG3 in multiple cancer types can suppress various microRNAs, thereby inhibiting the promotion of cancer phenotypes.
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