Non-Coding RNAs as Mediators of Epigenetic Changes in Malignancies

Abstract

Non-coding RNAs (ncRNAs) are untranslated RNA molecules that regulate gene expressions. NcRNAs include small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), circular RNAs (cRNAs) and piwi-interacting RNAs (piRNAs). This review focuses on two types of ncRNAs: microRNAs (miRNAs) or short interfering RNAs (siRNAs) and long non-coding RNAs (lncRNAs). We highlight the mechanisms by which miRNAs and lncRNAs impact the epigenome in the context of cancer. Both miRNAs and lncRNAs have the ability to interact with numerous epigenetic modifiers and transcription factors to influence gene expression. The aberrant expression of these ncRNAs is associated with the development and progression of tumors. The primary reason for their deregulated expression can be attributed to epigenetic alterations. Epigenetic alterations can cause the misregulation of ncRNAs. The experimental evidence indicated that most abnormally expressed ncRNAs impact cellular proliferation and apoptotic pathways, and such changes are cancer-dependent. In vitro and in vivo experiments show that, depending on the cancer type, either the upregulation or downregulation of ncRNAs can prevent the proliferation and progression of cancer. Therefore, a better understanding on how ncRNAs impact tumorigenesis could serve to develop new therapeutic treatments. Here, we review the involvement of ncRNAs in cancer epigenetics and highlight their use in clinical therapy.

Keywords: cancer; epigenetics; lncRNAs; miRNAs; ncRNAs.

Figure 1

MicroRNA (MiRNA) biogenesis pathway. Transcription of the miRNA gene by RNA polymerase Pol II or Pol III produces a primary transcript (priRNA) that is cleaved by the ribonuclease III Drosha and processed by the double-stranded RNA-binding protein Pasha in the nucleus. This results in the formation of a precursor miRNA (pre-miRNA) hairpin, which is exported from the nucleus via exportin-5-mediated translocation. Once in the cytoplasm, the pre-miRNA is cleaved by the RNase DICER in a complex with the double-stranded RNA-binding protein TRBP to generate a miRNA duplex. The non-functional strand of the miRNA duplex is subjected to degradation, while the mature miRNA (functional strand) binds to ARGONAUTE proteins and the RNA-induced silencing complex (RISC). The mature miRNA guides RISC to silence mRNA targets by cleavage, translational repression or deadenylation.

Figure 2

Long non-coding RNA (LncRNA)-mediated gene regulation mechanisms. Generally, lncRNAs originate from antisense transcripts produced by RNA polymerase II (Pol II). LncRNAs can be produced from diverse genomic locations, including introns, coding regions and sequences between genes. LncRNAs can recognize specific mRNA targets to modulate their expression by affecting post-transcriptional processes, including translation and mRNA stability. Alternatively, lncRNA can recruit proteins such as epigenetic regulators (activators or repressors) as a scaffolding system guided to regulate the expression of specific target genes. Additionally, lncRNAs can regulate specific gene expressions by functioning as competing endogenous RNAs (ceRNAs) capable of sequestering miRNAs.

Figure 3

Non-coding RNAs (NcRNAs) in cancer. A decrease in cell cycle arrest and apoptosis, along with an increase in cell proliferation, are hallmarks of cancer cells associated with solid tumors and hematological malignancies. NcRNAs can regulate these cancer hallmarks by the direct targeting of cancer-promoting genes involved in the cell cycle, apoptosis and proliferation or by targeting epigenetic factors that modulate the expression of such genes. Additionally, lncRNAs can regulate the expression of cancer-promoting genes by functioning as scaffolds to recruit epigenetic factors or by acting as ceRNAs.

Figure 4

Environmental factors impact the link between the epigenome and ncRNAs. Environmental factors, including dietary changes and exposure to carcinogens, can affect the expression of epigenetic regulatory complexes targeting the regulation of ncRNAs. Epigenetic modulation can either upregulate or downregulate the expression of ncRNAs, which, in turn, feed back onto the epigenetic landscape, promoting the gene expression profiles involved in carcinogenesis.