Long non-coding RNAs as an epigenetic regulator in human cancers

Abstract

Recent studies have described the important multiple roles of long non-coding RNAs (lncRNAs) during oncogenic transformation. Because the coding genome accounts for a small amount of total DNA, and many mutations leading to cancer occur in the non-coding genome, it is plausible that the dysregulation of such non-coding transcribes might also affect tumor phenotypes. Indeed, to date, lncRNAs have been reported to affect diverse biological processes through the regulation of mRNA stability, RNA splicing, chromatin structure, and miRNA-mediated gene regulation by acting as miRNA sponges. Furthermore, accumulating studies have described the roles of lncRNAs in tumorigenesis; however, the precise mechanisms of many lncRNAs are still under investigation. Here, we discuss recently reported mechanistic insights into how lncRNAs regulate gene expression and contribute to tumorigenesis through interactions with other regulatory molecules. We especially highlight the role of taurine upregulated gene 1, which was recently reported to have biological functions related to gene regulation, and discuss the future clinical implications of lncRNAs in cancer treatments.

Keywords: Chromatin structure; epigenetics; non-coding RNA; transcription modulators; treatment.

Figure 1

Multiple long non‐coding RNA (lncRNA) mechanisms of gene regulation, which rely on interactions with multiple molecules. In the nucleus, lncRNAs regulate gene expression by controlling the local chromatin structure or recruiting regulatory molecules to specific loci. In the cytoplasm, lncRNAs interact with other types of RNA and affect functions including mRNA stability, mRNA translation, or microRNA (miRNA) sponge. CDS, coding sequence; circRNA, circular RNA; Pol II, RNA polymerase II.

Figure 2

Aberrant signal transduction induces long non‐coding RNA (lncRNA) dysregulation in cancer cells. (a) Notch triggers oncogenic activity by the activation of two different lncRNAs (leukemia‐induced non‐coding activator RNA [LUNAR1] and taurine upregulated gene 1 [TUG1]) in cancers. LUNAR1 enhances insulin‐like growth factor 1 receptor (IGF1R) expression through a cis‐activation mechanism in leukemia (left). TUG1 coordinately promotes self‐renewal by sponging microRNA‐145 (miR‐145) in the cytoplasm and recruiting polycomb repressive complex 2 (PRC2) to repress differentiation genes by the locus‐specific methylation of histone H3K27 by YY1 binding activity in glioma stem cells. Me, methylation; Pol II, RNA polymerase II. (b) LncRNA activated by transforming growth factor‐β (TGF‐β) (lncRNA‐ATB) is upregulated by TGF‐β signaling in hepatocellular carcinoma. LncRNA‐ATB upregulates Zinc finger E‐box‐binding homeobox (ZEB)1 and ZEB2 by sequestering miR‐200 family members (miR‐200s) and inducing epithelial mesenchymal transition and invasion. In addition, lncRNA‐ATB promotes the organ colonization of tumor cells by binding to interleukin (IL)‐11 mRNA.

Figure 3

Inhibition of taurine upregulated gene 1 (TUG1) by an antiTUG1 drug delivery system (DDS) in a mouse xenograft model. Mice bearing brain tumors were given i.v. antisense oligonucleotide (ASO) targeting TUG1 coupled with a potent DDS using cyclic Arg‐Gly‐Asp peptide‐conjugated polymeric micelle (antiTUG1‐DDS). AntiTUG1‐DDS was specifically accumulated and retained in the tumors and markedly reduced tumor growth.9 Tumor areas are surrounded by red dotted line.