Brain Tumor Res Treat 2014;2(1):1-6 / pISSN 2288-2405 / eISSN 2288-2413 REVIEW ARTICLE http://dx.doi.org/10.14791/btrt.2014.2.1.1 Roles of Long Non-Coding RNAs on Tumorigenesis and Glioma Development Ju Young Park1*, Jeong Eun Lee1*, Jong Bae Park2,3, Heon Yoo2,3, Seung-Hoon Lee2,3, Jong Heon Kim1,3 1Cancer Cell and Molecular Biology Branch, 2Specific Organs Cancer Branch, Research Institute, National Cancer Center, Goyang, Korea 3Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea More than 98% of eukaryotic transcriptomes are composed of non-coding RNAs with no functional Received March 19, 2014 protein-coding capacity. Those transcripts also include tens of thousands of long non-coding RNAs Revised March 27, 2014 (lncRNAs) which are emerging as key elements of cellular homeostasis, essentially tumorigenesis Accepted March 31, 2014 steps. However, we are only beginning to understand the nature and extent of the involvement of ln- Correspondence cRNAs on tumorigeneis. Here, we highlight recent progresses that have identified a myriad of molecu- Jong Heon Kim lar functions on tumorigenesis for several lncRNAs including metastasis-associated lung adenocarci- Cancer Cell and Molecular Biology noma transcript 1 (MALAT1), prostate cancer associated non-coding RNA 1 (PRNCR1), prostate cancer Branch, Research Institute, National gene expression marker 1 (PCGEM1), H19, and homeobox transcript antisense intergenic RNA (HO- Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 410-769, Korea TAIR), and several new lncRNAs for glioma development. Potential therapeutic approaches for the ln- Tel: +82-31-920-2204 cRNAs in various human diseases are also discussed. Fax: +82-31-920-2006 E-mail: [email protected] Key Words Non-coding RNA; lncRNA; Tumorigenesis; Glioma. *These two authors contributed equally to this work. INTRODUCTION coding RNA (lncRNA) by their lengths, and sometimes ncRNAs are subdivided by function, loci, and post-transcrip- The global human genome project was launched in the tional modification. Among these, most onco-molecular biol- 1990’s and researchers expect to understand information of ogists are deeply interested in the short ncRNAs [e.g., microR- the whole human genome, especially genes which encode NAs (miRNAs)] [6] and very recently lncRNAs for their functional proteins. However, they recognized that the human research projects as an aspect of gene expression regulation genome contains only about 20000 protein-coding genes [1,2]. [7-11]. This review, we essentially highlight and introduce our It is not surprising that the numbers of protein-coding genes recent understanding of roles of lncRNAs in tumorigenesis, are pretty similar in number to those of Caenorhabditis elegans. including glioma development. Because the protein-coding genes could not properly explain the human gene expression complexity in view of physiologi- LNCRNAS: MODE OF ACTION cal and evolutional aspects, investigators have suspected that the potential non-protein coding but transcriptionally active Recent reports showed that lncRNAs have multifunctional genes (>98% of transcribed genes) may be fully accountable roles on modulating embryonic pluripotency, differentiation, for gene expression complexity of human [3-5]. development, and various diseases, essentially in cancers [7-11]. Recently, investigators categorized the non-coding RNAs Therefore, dysregulation of lncRNAs has been shown to be as- (ncRNAs) as short ncRNA, mid-size ncRNA, and long non- sociated with a broad range of defects on those physiological phenomena. lncRNAs may be classified according to their This is an Open Access article distributed under the terms of the Creative Commons mode of action and functions in cells such as, 1) mediators on Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any signaling pathway, 2) serving as molecular decoys, 3) work as medium, provided the original work is properly cited. molecular guides for the ribonucleoprotein complexes to cer- Copyright © 2014 The Korean Brain Tumor Society and The Korean Society for Neuro-Oncology 1 lncRNA on Tumorigenesis tain specific chromatin site, and also have 4) scaffold function lncRNAs: work as molecular guides for the proper complex formation (Fig. 1) [11]. lncRNAs can serve as the molecular guides by locating cer- tain ribonucleoprotein complexes to a specific target site on lncRNAs: mediators on signaling pathway the chromatin (Fig. 1C) [14]. The gene expression can be al- In most cases, transcription of lncRNAs is temporally reg- tered either in neighboring genes (in cis) or distantly located ulated and the expression has tissue specificity. Moreover, their ones (in trans). expression is modulated in response to the internal and exter- nal stimuli [12]. Therefore, lncRNAs may serve as molecular lncRNAs: scaffold function signaling mediators which modulate a certain set of gene ex- lncRNAs can support the assembly of protein complexes pression temporally and even spatially (Fig. 1A). which link the factors together to generate brand new func- tions (Fig. 1D). Some lncRNAs possess distinct protein-bind- lncRNAs: molecular decoys ing domains that combine each molecule together. This event lncRNAs may serve as molecular decoys which take pro- may have impact on action of transcription or repression. teins or RNAs away from a specific location. Sometimes decoy lncRNAs can serve as “sponge” to proteins (e.g., transcription LNCRNAS ON TUMORIGENESIS factors and chromatin modifiers) and small ncRNAs (e.g., miRNAs) (Fig. 1B) [13]. This event can lead to overall tran- Generally the lncRNAs designate ncRNAs which is more scriptome change of cells. than 200 nt long [7-11]. 1) Usually those modulate DNA meth- ylation which is closely related with genome imprinting (e.g., Stimuli Transcription factor or chromatin modifier Transcription Activated status of lncRNA Transcription lncRNA factor A Gene activation B Gene suppression Y lncRNA X Z Proteins lncRNA Assembly of Formation of ribonucleo- protein X protein complex complex Z Y DNA modification Changes in gene expression C D Transcriptional activation or repression Fig. 1. Schematic diagram of lncRNA action mechanisms. A: Mediators on signaling pathway: lncRNAs can serve as molecular signaling mediators which modulate certain set of gene expression in conjunction with specific transcription factors or chromatin modifiers. B: Molec- ular decoys: lncRNAs can serve as the molecular decoy which takes away proteins or RNAs from the specific location. C: Work as molecu- lar guides: lncRNAs can serve as the molecular guides by locating certain ribonucleoprotein complexes to specific target site on chromatin. D: Scaffold function: lncRNAs can support the assembly of protein complexes which link the factors together to generate brand new func- tions. IncRNA: long non-coding RNA. 2 Brain Tumor Res Treat 2014;2(1):1-6 JY Park et al. X-chromosome inactivation by lncRNA XIST) [15]. 2) Several morigeneis. As the lncRNAs 1) metastasis-associated lung ad- large intergenic non-coding RNAs (lincRNAs) which locate enocarcinoma transcript 1 (MALAT1) and 2) prostate cancer intergenic (gene to gene) region induced by tumor suppressor associated non-coding RNA 1 (PRNCR1), prostate cancer p53 in response to DNA damage (e.g., lincRNA-p21) [16]. 3) gene expression marker 1 (PCGEM1), and as the lincRNA 3) The ultra-conserved region (UCR) is extremely conserved H19 and 4) homeobox transcript antisense intergenic RNA DNA sequences among species which is more than 200 nt (HOTAIR) are discussed. long [17,18]. From this region the lncRNA T-UCR is tran- scribed actively. Although the exact physiological roles of T- lncRNA MALAT1 UCR have not been reported yet, however investigators as- The lncRNA MALAT1 is a 7-kb long, spliced non-coding sumed that T-UCRs have existed from early evolution stage, RNA, also known as non-coding nuclear-enriched abundant and have special roles for interacting with miRNA or different transcript 2 (NEAT2), which is highly conserved amongst distribution in tissues. mammals and dominantly expressed in the nucleus [21]. In- In most cases lncRNAs are involved in transcriptional regu- terestingly, a conserved tRNA-like sequence at the 3ʹ end is lation [19]. The lncRNAs can be classified by their action cleaved off and processed to generate a short tRNA-like mechanisms, 1) acting in cis; the lncRNA transcription affects ncRNA, MALAT1-associated small cytoplasmic RNA (mas- the surrounding coding gene expression, 2) modulating his- cRNA) [22]. Moreover, MALAT1 modulates the speckle as- tone modification [14,20], and 3) acting in trans; XIST induces sociation of a subset of pre-mRNA splicing factors [23-25]. X-chromosome inactivation of female [15]. MALAT1 RNA is usually overexpressed in cancer tissues, Recent reports showed that the dysfunction of lncRNAs is and overexpression of MALAT1 is associated with cell hyper- closely associated with tumor formation, proliferation, inva- proliferation and metastasis [21,26]. Some reports showed that sion, and metastasis [3,8,9,11]. In this review, we highlight MALAT1 regulates the expression of metastasis-associated several essential lncRNAs which are closely related with tu- genes and MALAT1 regulates expression of cell cycle genes siRNA Antisense oligo Ribozyme or deoxyribozyme RISC RNase H A Silencing of lncRNA B Cleavage of lncRNA C Cleavage of lncRNA