Long noncoding RNAs in cancer: mechanisms of action and technological advancements
Bartonicek et al. Molecular Cancer
Long noncoding RNAs in cancer: mechanisms of action and technological advancements
Nenad Bartonicek 0 2
Jesper L. V. Maag 0 1 2
Marcel E. Dinger 1 2
0 Equal contributors
1 Faculty of Medicine, St Vincent's Clinical School, University of New South Wales , Sydney, NSW , Australia
2 Genome Informatics, Genomics & Epigenetics Division, Garvan Institute of Medical Research , Sydney, NSW , Australia
The previous decade has seen long non-coding RNAs (lncRNAs) rise from obscurity to being defined as a category of genetic elements, leaving its mark on the field of cancer biology. With the current number of curated lncRNAs increasing by 10,000 in the last five years, the field is moving from annotation of lncRNA expression in various tumours to understanding their importance in the key cancer signalling networks and characteristic behaviours. Here, we summarize the previously identified as well as recently discovered mechanisms of lncRNA function and their roles in the hallmarks of cancer. Furthermore, we identify novel technologies for investigation of lncRNA properties and their function in carcinogenesis, which will be important for their translation to the clinic as novel biomarkers and therapeutic targets.
Background
Our understanding of cancer biology was drastically
changed by the genomic revolution of the last decade,
marked by the conclusion of the human genome project
and the development of novel DNA sequencing
technologies [
1, 2
]. The complete human genome sequence
provided a framework for comparison of populations
with cancer susceptibility, allowing for clinical prognosis
based on mutations in genes such as BRCA1/2 or
differential treatment based modifications in KRAS and BRAF
[
3–5
]. Sequencing of individual tumours revealed the
prevalence of acquired DNA damage compared to the
germline mutations, which allowed identification of
footprints for individual mutagens and gave us important
insights into tumour heterogeneity and evolution [
6–10
].
Parallel to the progress in genomics, advances in
transcriptomics initiated functional annotation of numerous
genomic loci associated with cancer that do not overlap
protein-coding genes – the noncoding genome.
Large-scale cDNA sequencing projects, together with
technological advancements such as tiling arrays and the
next generation RNA sequencing provided an
unprecedented view of the transcriptome complexity [
11–15
].
Surprisingly, only 1–2 % of the whole genome encodes
proteins, with evidence of at least 80 % of the remainder
being actively transcribed [
11, 16
]. These non-coding
portions of the genome produce a large variety of mostly
regulatory RNAs that differ in their biogenesis,
properties and function, and are separated by their size into
short, such as miRNAs (reviewed in [17]) and long
(>200 nt) RNAs [
12, 18–20
]. The heterogeneous
category of long non-coding RNAs (lncRNA) are especially
abundant, accounting for 16,000 curated records in the
current Gencode annotation (v.23) [21] with for all
lncRNA loci in the human genome numbering as high
as 60,000 [
22
].
lncRNAs remained elusive even in the genomics era due
to their low expression levels and their presence in specific
cell types, tissues or narrow time frames [
23–25
]. They
were identified as a class of RNA molecules in 2002 [
26
],
even though some lncRNA such as H19 and Xist were
known since the early 1990s [
27, 28
] Analogous to protein
coding genes but with low coding potential, these RNAs
are usually transcribed by RNA polymerase II (Pol II),
spliced, and mostly polyadenylated [
12, 13
]. Similarly,
lncRNA promoters are enriched for active histone
modifications typical of Pol II occupancy: H3K4me3, H3K9ac and
H3K27ac [
20, 29
]. Even though the sequence of lncRNAs
evolves rapidly, especially compared to their 3D structure,
their tissue specificity as well as promotor sequences
remain conserved as protein-coding genes [
30–32
]. The
heterogeneity of lncRNAs resonates in the diversity of their
functions; lncRNAs interact with DNA, proteins and other
RNAs to participate in processes from transcription,
intracellular trafficking to chromosome remodelling as reviewed
previously [
29, 33
]).
lncRNAs have been observed to regulate complex cellular
behaviours such as growth, differentiation and
establishment of cell identity that are commonly deregulated in
cancer [
34–36
]. Some have already been linked to poor
prognosis in multiple tumour types and have a clinical
relevance as biomarkers. In this review we will focus on the
molecular mechanisms of function for cancer-associated
lncRNAs, their involvement in cancer hallmarks and
provide information on the most recent advances in
technologies for their identification and functional interrogation.
Identification of lncRNAs in cancer
lncRNAs were initially observed in carcinogenesis due to
their differential expression compared to normal tissues.
High expression in tumour (...truncated)