The emergence of lncRNAs in cancer biology

Abstract

The discovery of numerous noncoding RNA (ncRNA) transcripts in species from yeast to mammals has dramatically altered our understanding of cell biology, especially the biology of diseases such as cancer. In humans, the identification of abundant long ncRNA (lncRNA) >200 bp has catalyzed their characterization as critical components of cancer biology. Recently, roles for lncRNAs as drivers of tumor suppressive and oncogenic functions have appeared in prevalent cancer types, such as breast and prostate cancer. In this review, we highlight the emerging impact of ncRNAs in cancer research, with a particular focus on the mechanisms and functions of lncRNAs.

Keywords: cancer; epigenetics; lncRNA; long noncoding RNA.

Figure 1. MicroRNA-mediated pathways in cancer

(A) MicroRNA (miRNA) transcription usually occurs by RNA Polymerase II, generating a primary pri-miRNA transcript. The pri-miRNA is processed by DROSHA and cleaved by DICER to generate a mature miRNA, which then associates with Argonaute family proteins in the RNA-induced silencing complex (RISC) to achieve gene expression control. (B) In cancer, aberrant miRNA expression levels can lead either to the repression of tumor suppressor (typically when miRNA levels are upregulated) or de-repression of oncogenes (typically when miRNA levels are downregulated). The colored triangles indicate different miRNA binding sites in the 3’ untranslated region (UTR) of a protein-coding mRNA. Abbreviation: CDS, coding sequence. (C) Two examples of aberrant miRNA signaling in cancer are let-7, which is downregulated in cancer and regulates oncogenes such as cMYC, and miR-10b, which is upregulated in cancer metastases and indirectly upregulates RHOC.

Figure 2. Gene expression regulation by lncRNAs

(A) and (B): cis-regulation of gene expression results in local control of genes neighboring, or on the same chromosome as, lncRNA transcription. (A) H19 and KCNQ1OT1 are imprinted lncRNAs on chromosome 11 associated with allele-specific expression of IGF2 and KCNQ1. (B) XIST transcription facilitates inactivation of an individual X chromosome in women by recruiting the Polycomb Repressive Complex 2 (PRC2). (C) and (D) trans-regulation of gene expression results in control of genomically-distant genes. (C) HOTAIR is transcribed from the HoxC cluster on chromosome 12 but represses the HoxD locus via PRC2-mediated epigenetic modifications. (D) PCAT-1 is transcribed from chromosome 8 but regulates target genes such as BRCA2, CENPE, and CENPF, thereby impacting cell proliferation. (E) The GAS5 lncRNA binds Glucocorticoid Receptor (GR) and sequesters it, preventing upregulation of GR-target genes across the genome. The blue line represents the GAS5 transcript.

Figure 3. Mechanisms of lncRNA function

(A) lncRNAs, such as HOTAIR, may serve as a scaffolding base for the coordination of epigenetic or histone-modifying complexes, including Polycomb repressive complexes and LSD1/CoREST. (B) Enhancer RNAs (eRNAs) transcribed from gene enhancers may facilitate hormone signaling by cooperating with lineage-specific complexes such as FOXA1 and Androgen Receptor. (C) lncRNAs may directly impact tumor suppressor signaling either by transcriptional regulation of tumor suppressor genes through epigenetic silencing (e.g. ANRIL, upper) or by mediating activation of tumor suppressor target genes (e.g. linc-p21, lower). (D) MALAT1 and NEAT2 lncRNAs may be integral components of the nuclear paraspeckle and contribute to post-transcriptional processing of mRNAs. (E) Gene expression regulation may occur through direct lncRNA-mRNA interactions which arise from hybridization of homologous sequences and can serve as a signaling for STAU1-mediated degradation of the mRNA. (F) RNA molecules, including mRNAs, pseudogenes, and ncRNAs, can serve as molecular sponges for miRNAs. This generates an environment of competitive binding of miRNAs to achieve gene expression control based upon the degree of miRNA binding to each transcript. The colored triangles represent different miRNA binding sites in a transcript. Abbreviation: CDS, coding sequence.

Figure 4. Clinical implications of lncRNAs

(A) The PCA3 urine biomarker test for prostate cancer employs a non-invasive approach to disease diagnosis by collecting patient urine samples, isolating nucleic acids from cells in the urine sediment, and quantifying PCA3 expression. (B) lncRNA-based therapies may target the lncRNA by utilizing either RNA interference (RNAi), which uses sequence homology between the lncRNA and the RNAi therapeutic molecule, or a small molecule therapy that interacts with the lncRNA. These therapeutic avenues may be appropriate for systemic therapy by either intravenous or oral administration. (C) Genome-wide association studies (GWAS) may provide germline polymorphisms that predict an individual patient’s clinical risk for disease development, response to therapy, or disease aggressiveness, while also providing molecular information through the impact of polymorphisms on gene expression of key genes. Abbreviation: CDS, coding sequence.