LncRNAs in Cancer: From garbage to Junk

Abstract

Sequencing-based transcriptomics has significantly redefined the concept of genome complexity, leading to the identification of thousands of lncRNA genes identification of thousands of lncRNA genes whose products possess transcriptional and/or post-transcriptional regulatory functions that help to shape cell functionality and fate. Indeed, it is well-established now that lncRNAs play a key role in the regulation of gene expression through epigenetic and posttranscriptional mechanims. The rapid increase of studies reporting lncRNAs alteration in cancers has also highlighted their relevance for tumorigenesis. Herein we describe the most prominent examples of well-established lncRNAs having oncogenic and/or tumor suppressive activity. We also discuss how technical advances have provided new therapeutic strategies based on their targeting, and also report the challenges towards their use in the clinical settings.

Keywords: epigenetics; oncogenic lncRNAs; therapeutic targeting; translational reprogramming; tumor suppressor lncRNAs.

Figure 1

LncRNAs in epigenetic regulation of gene expression. Schematic models of (1) trans-acting lncRNAs recruiting histone deacetylases (HDACs, upper left), histone methyltransferases (HMTs, upper right) associated to gene repression, or histone acetylases (HATs, lower left) and histone demethylases (HDMs, lower right) associated to transcription-permissive chromatin; (2) enancher RNA (eRNA) recruiting the Mediator complex—with cohesin-based stabilizing contacts—responsible for DNA looping and distal transcriptional activation of target genes; (3) lncRNAs interacting with nucleosome destabilizing proteins, such as the SWI/SNF complex (left), causing nucleosome exclusion and gene activation, or with remodeling proteins (NRPs, right) associated with chromatin condensation and transcriptional repression; and (4) lncRNA acting as a scaffold for DNA methyltransferases (DNMTs) and DNA-binding proteins (DBP), and driving gene promoters’ methylation and their transcriptional repression.

Figure 2

LncRNAs in translation regulation. In the nucleus, lncRNAs PAPAS and SLERT regulate ribosome biogenesis through regulation of rRNA transcription, while Zeb2-NAT by base-paring to its sense coding gene Zeb2, causes inclusion of an IRES thus leading to its translation. In the cytoplasm, lncRNAs ZFAS1 binds the small ribosomal subunit and may have a role in mRNA translation. NBR2 attenuates global translation by interacting with AMPK and promoting its kinase activity. LincRNA-p21 regulates specific mRNA-targets by promoting their interaction with the translational repressors.

Figure 3

LncRNAs involved in different cancer types. Main examples of lncRNAs with oncogenic (red) or tumor-suppressive (green) properties reported in different tumors (i.e., clockwise from top left: neuroblastoma, melanoma, lung c., breast c., ovarian c., colon c., pancreatic c., hepatocellular c., prostate c., osteosarcoma, leukemia, gastric c., papillary thyroid c.). AML = acute myeloid leukemia; APL = acute promyelocytic leukemia; CML = chronic myeloid leukemia.