Long noncoding RNAs in cancer: mechanisms of action and technological advancements

Molecular Cancer, May 2016

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.

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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)


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Nenad Bartonicek, Jesper Maag, Marcel Dinger. Long noncoding RNAs in cancer: mechanisms of action and technological advancements, Molecular Cancer, 2016, pp. 43, 15, DOI: 10.1186/s12943-016-0530-6