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The Hallmarks of Cancer a Long Non-Coding RNA Point of View

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review REVIEW RNA Biology 9:6, 703-719; June 2012; © 2012 Landes Bioscience The hallmarks of cancer A long non-coding RNA point of view Tony Gutschner and Sven Diederichs* Helmholtz-University-Group “Molecular RNA Biology & Cancer”; German Cancer Research Center DKFZ; Heidelberg, Germany; Institute of Pathology; University of Heidelberg; Heidelberg, Germany Keywords: non-coding RNA, ncRNA, lincRNA, gene expression, carcinogenesis, tumor biology, cancer therapy, MALAT1, HOTAIR, XIST, T-UCR Abbreviations: ALT, alternative lengthening of telomeres; AR, androgen receptor; ANRIL, antisense non-coding RNA in the INK4 locus; Bax, BCL2-associated X protein; Bcl-2, B cell CLL/lymphoma 2; Bcl-xL, B cell lymphoma-extra large; CBX, chromobox homolog; cIAP2, cellular inhibitor of apoptosis; CUDR, cancer upregulated drug resistant; EMT, epithelial- mesenchymal-transition; eNOS, endothelial nitric-oxide synthase; ER, estrogen receptor; GAGE6, G antigene 6; GAS5, growth-arrest specific 5; GR, glucocorticoid receptor; HCC, hepatocellular carcinoma; HIF, hypoxia-inducible factor; HMGA1, high mobility group AT-hook 1; hnRNP, heterogenous ribonucleoprotein; HOTAIR, HOX antisense intergenic RNA; HOX, homeobox; HULC, highly upregulated in liver cancer; lncRNA, long non-coding RNA; lincRNA, long intergenic RNA; MALAT1, metastasis associated long adenocarcinoma transcript 1; Mdm2, murine double minute 2; miRNA, microRNA; mRNA, messenger RNA; mTOR, mammalian target of rapamycin; Myc, myelocytomatosis oncogene; NAT, natural antisense transcript; ncRNA, non-coding RNA; NEAT2, nuclear-enriched abundant transcript 2; NSCLC, non-small cell lung cancer; PANDA, P21 associated ncRNA DNA damage activated; PAR-CLiP, photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation; PCA3, prostate cancer gene 3; PCAT-1, prostate cancer associated transcript 1; piRNA, PIWI-interacting RNA; PCGEM1, prostate-specific transcript 1; POT1, protection of telomeres 1; PR, progesterone receptor; PRC, polycomb repressive complex; PRNCR1, prostate cancer non-coding RNA 1; PSF, PTB-associated splicing factor; P-TEFb, positive transcription elongation factor b; PTEN, phosphatase and tensin homolog; Puma, p53-upregulated modulator of apoptosis; qRT- PCR, quantitative reverse transcription-polymerase chain reaction; RB, retinoblastoma; RIP-Seq, RNA immunoprecipitation and sequencing; rRNA, ribosomal RNA; siRNA, small interfering RNA; snRNA, small nuclear RNA; snoRNA, small nucleolar RNA; SPRY4-IT1, sprouty homolog 4 intronic transcript 1; SRA, steroid receptor RNA activator; SUZ12, suppressor of zeste 12 homolog; TERC, telomerase RNA component; TERRA, telomeric repeat-containing RNA; TERT, telomerase reverse transcriptase; tie-1AS, tyrosine kinase containing immunoglobulin and epidermal growth factor homology domain-1 antisense transcript; TP53, tumor protein 53; tRNA, transfer RNA; T-UCR, transcribed ultra-conserved genomic region; VEGF-A, vascular endothelial growth factor-A; Xist, X inactive-specific transcript With the advent of next generation sequencing methods and Introduction progress in transcriptome analysis, it became obvious that the human genome contains much more than just protein-coding In 2001, the human genome sequencing consortium released its genes. In fact, up to 70% of our genome is transcribed into RNA final draft of the human genome.1 Based on this work, the com- that does not serve as templates for proteins. In this review, we plete human transcriptome could be identified and characterized focus on the emerging roles of these long non-coding RNAs in recent years mainly due to the development of two new tech- (lncRNAs) in the field of tumor biology. Long ncRNAs were niques: deep sequencing and DNA tiling arrays. These methods found to be deregulated in several human cancers and show revolutionized our view of genome organization and content as tissue-specific expression. Functional studies revealed a broad they revealed an unexpected finding: a much larger part of the spectrum of mechanisms applied by lncRNAs such as HOTAIR, human genome is pervasively transcribed into RNA than previ- MALAT1, ANRIL or lincRNA-p21 to fulfill their functions. Here, ously assumed. It is estimated that up to 70% of the genome we link the cellular processes influenced by long ncRNAs to the hallmarks of cancer and therefore provide an ncRNA point- is transcribed but only up to 2% of the human genome serve 2-6 of-view on tumor biology. This should stimulate new research as blueprints for proteins. RNA molecules that lack protein- directions and therapeutic options considering long ncRNAs coding potential are collectively referred to as non-coding RNAs as novel prognostic markers and therapeutic targets. (ncRNAs) and well-known ncRNAs are classical “housekeep- ing” RNAs, such as tRNAs (tRNAs), rRNAs (rRNAs), small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs), which are constitutively expressed and play critical roles in pro- *Correspondence to: Sven Diederichs; Email: [email protected] tein biosynthesis. Submitted: 03/01/12; Revised: 04/18/12; Accepted: 04/23/12 http://dx.doi.org/10.4161/rna.20481 www.landesbioscience.com RNA Biology 703 Long ncRNAs: What, Where and Why? very limited. However, recently it became obvious that lncRNAs play an important role in regulating gene expression at various According to their size, ncRNAs are subdivided into two groups: levels, including chromatin modification, transcription and post- small ncRNAs (< 200 nt) and long ncRNAs. In recent years, transcriptional processing.16,35 For example, the lncRNAs Xist small ncRNAs like microRNAs (miRNAs), small interfering (X inactive-specific transcript) or HOTAIR (HOX Antisense RNAs (siRNAs) or PIWI-interacting RNAs (piRNAs) received Intergenic RNA) interact with chromatin remodeling complexes most attention and especially miRNAs were shown to play many to induce heterochromatin formation in specific genomic loci important roles in cancer.7-9 However, it has become increas- leading to reduced target gene expression.23,36-38 Long ncRNAs ingly clear that mammalian genomes encode also numerous can also function by regulating transcription through a variety of long ncRNAs, defined as endogenous cellular RNAs of more mechanisms that include interaction with RNA binding proteins, than 200 nucleotides in length that lack an open reading frame acting as a co-activator of transcription factors, or repressing a of significant length (less than 100 amino acids).10-13 Therefore, major promoter of their target gene.39-41 In addition to chroma- long ncRNAs (lncRNAs) constitute a very heterogeneous group tin modification and transcriptional regulation, long ncRNAs of RNA molecules that allows them to cover a broad spectrum can modulate gene expression at the post-transcriptional level of molecular and cellular functions by implementing different or splicing level.42-44 In Figure 1 we provide an overview about modes of action. lncRNA functions. However, this is only a snapshot of our cur- Originally, lncRNAs were discovered via large-scale sequenc- rent knowledge and more functional insights might be obtained ing of full-length cDNA libraries in the mouse.14 Other names in the future. Consequently, if we want to fully understand the such as large RNA, macroRNA and long intergenic ncRNA (lin- complex mechanisms underlying malignant processes, e.g., car- cRNA) are also used to refer to these. LncRNAs often overlap cinogenesis, metastasis and drug resistance, we need to consider with or are interspersed between coding and non-coding tran- this family of regulatory transcripts that add a new layer of com- scripts.4,15,16 From a genetic point of view long, ncRNAs fall into plexity to biology. one or more of five broad categories: (1) sense or (2) antisense, when overlapping one or more exons of another transcript on the Hallmarks of Cancer: The Basics same or opposite strand, respectively; (3) bidirectional, when the expression of it and a neighboring coding transcript on the oppo- Cancer is one of the leading causes of death worldwide and site strand is initiated in close genomic proximity, (4) intronic, accounted for 7.6 million (13% of all deaths) in 2008.45 In the when derived from an intron of a second transcript; or (5) inter- US, for example, lifetime probability of developing cancer is genic, when it lies as an independent unit within the genomic ~44% for men or ~38% for women, respectively.46 Determining interval between two genes.12 the causes of cancer is a complex issue, but well-known risk fac- Several studies were conducted to identify lncRNAs in the tors are alcohol and tobacco abuse, infections, radiation, obesity human genome.17-24 A recent study identified 5,446 lncRNA and a lack of physical activity. genes in the human genome and combined them with long Although “cancer” comprises a heterogeneous group of dis- ncRNAs from four published sources to derive 6,736 long eases, one characteristic and unifying feature is the creation of ncRNA genes.25 This study also investigated the protein-cod- abnormal cells that grow beyond their natural boundaries. In ing capacity of known genes overlapping with lncRNAs and 2000, Hanahan and Weinberg proposed six hallmarks of cancer revealed that 62% of known genes with “hypothetical protein” that all together form the fundamental principle of this malig- names lacked protein-coding capacity and this might even fur- nant transformation.47 Since tumor formation is a multistep ther enlarge the catalog of human lncRNAs. process, normal cells
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