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Emerging Roles of Lncrnas in the Post-Transcriptional Regulation In Genes & Diseases (2019) 6,6e15 Available online at www.sciencedirect.com ScienceDirect journal homepage: http://ees.elsevier.com/gendis/default.asp REVIEW ARTICLE Emerging roles of lncRNAs in the post-transcriptional regulation in cancer Rong-Zhang He a,b,c, Di-Xian Luo b, Yin-Yuan Mo c,* a Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410078 Hunan, China b Translational Medicine Institute, National & Local Joint Engineering Laboratory for High-through Molecular Diagnosis Technology, Collaborative Research Center for Post-doctoral Mobile Stations of Central South University, Affiliated the First People’s Hospital of Chenzhou of University of South China, Chenzhou, 432000, China c Department of Pharmacology/Toxicology, and Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA Received 20 December 2018; accepted 21 January 2019 Available online 11 February 2019 KEYWORDS Abstract Accumulating evidence indicates that long non-coding RNAs (lncRNAs) can play a Alternative splicing; pivotal role in regulation of diverse cellular processes. In particular, lncRNAs can serve as mas- LncRNA; ter gene regulators at transcriptional and posttranscriptional levels, leading to tumorigenesis. Posttranscriptional In this review, we discuss latest developments in lncRNA-meditated gene expression at the regulation; post-transcriptional level, including gene splicing, mRNA stability, protein stability and nuclear Protein stability; trafficking. RNA binding proteins; Copyright ª 2019, Chongqing Medical University. Production and hosting by Elsevier B.V. This is RNA stability an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/). Introduction small fraction of total transcripts.1,2 The rest of transcripts are non-coding RNAs, including microRNAs and long non- coding RNAs (lncRNAs). These non-coding transcripts were The advances in functional genomics have revealed that 3 although large numbers of RNAs are transcribed from the initially considered as transcriptional noises, however it human genome, protein coding genes account for a very has become increasingly apparent that they may play a critical role in diverse cellular processes from normal development to disease processes.4e7 There are two major classes of non-coding RNAs based on their size, 1) small * Corresponding author. ncRNAs less than 200 nt in length, represented by micro- E-mail address: [email protected] (Y.-Y. Mo). RNAs and 2) long non-coding RNAs (lncRNAs) larger than Peer review under responsibility of Chongqing Medical 200 nt in length. MicroRNA are well characterized and are University. https://doi.org/10.1016/j.gendis.2019.01.003 2352-3042/Copyright ª 2019, Chongqing Medical University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). LncRNA-mediated post-transcriptional regulation in cancer 7 known to induce mRNA degradation or block mRNA trans- RNA binding proteins (RBPs). Interaction of lncRNAs with lation via the RNA interference pathway.8 On the other these proteins to form RNP complexes is critical for lncRNAs to hand, lncRNAs are less well characterized. As a matter of exert their function as gene regulators. There are numerous fact, little is known for their functions for the vast majority examples of such interactions. Among them is the interaction of lncRNAs. To date, the non-code database lists over of lncRNAs with RBPs such as chromatin remodeling enzymes 96,000 human lncRNAs (http://www.noncode.org), such as EZH2 and PRC2.16,20 As a histone methyltransferase, whereas more than 56,000 human lncRNAs have been EZH2 is a phosphorylated protein when it is active; and the catalogued on LNCipedia (http://www.lncipedia.org), and phosphorylation at threonine residue 345 has been shown to the number of lncRNAs continues to grow.9e11 be critical to its interaction with HOTAIR.27 Similarly, linc- Multiple studies have shown that a significant number of HOXA1 RNA represses Hoxa1 by interaction with the protein lncRNAs are emerging as key players in various layers of PURB as a transcriptional cofactor.28 LincRNA-p21 has been cellular processes.12,13 Although we are just beginning to shown to be a p53 transcriptional target.29 When lincRNA-p21 understand the function of lncRNAs, increasing evidence binds to hnRNP K to form a RNP complex, this complex me- suggests that lncRNAs may positively or negatively regulate diates global gene repression and apoptosis in the p53 gene expression at the transcriptional and/or post- pathway. On the other hand, PANDA (P21 associated ncRNA transcriptional level.14,15 The focus of this review is on post- DNA damage activated) is able to block apoptosis through transcriptional regulation of gene expression by lncRNAs. interaction with the transcription factor NF-YA to limit expression of pro-apoptotic genes. Linc-RoR interacts with hnRNP I to suppress p53 in response to DNA damage.30 More- LncRNA-mediated gene expression over, hnRNP I can also interact with other lncRNAs such as UCA1 to suppress p27 expression.31 Finally, lncRNA CTBP1-AS Due to their role in regulation of gene expression, lncRNAs can interact with PSF to cause the global androgen-mediated have been implicated in control of a variety of cellular gene repression.32 These examples highlight the importance functions and disease processes such as stem cell mainte- of lncRNA-ribonucleoprotein complexes in gene regulation. nance and cancer metastasis.16e21 This may have to do with their ability to interact with DNA, RNA or protein. For example, lncRNAs may serve as 1) signals for transcription; Post-transcriptional regulation of gene 2) decoys to titrate transcription factors; 3) guides for expression chromatin-modifying enzymes to be recruited to target genes and 4) scaffolds to bring together multiple proteins to The post-transcriptional regulation involves the stability e form functional ribonucleoprotein complexes.12,22 24 and distribution of the different transcripts, such as alter- Apparently, the mechanism of lncRNA-mediated gene native splicing, nuclear degradation (exosome), processing, regulation is much more sophisticated than what we had and nuclear export, where RBPs often play an important previously anticipated. role. This may also include protein modifications and the LncRNAs function in many cases as transcriptional regu- protein subcellular localization. Alterations of these events lators. At the transcriptional level, lncRNAs may directly act have been implicated in tumorigenesis. on transcriptional complexes or serve as a scaffold to recruit In eukaryotes, after a gene is transcribed, an initial various components including RNA polymerase II or alter product of transcription is pre-mRNA, which is processed chromatin structure. LncRNAs can also function as critical into mature mRNA by removing introns in most cases. This players in controlling the remolding of chromatin structure. A process is also called gene splicing. In addition, RNA pro- good example is lncRNA HOTAIR that mediates the tran- cessing also includes other events such as mRNA export, scriptional silencing of HOXD locus via recruitment of the localization, translation and stability, which often involves polycomb chromatin remodeling complex,12,25 through which multiple protein factors, such as RBPs. RBPs achieve these lncRNAs can regulate large numbers of genes.26 events through an RNA recognition motif (RRM) that binds a At the post-transcriptional level, lncRNAs may interact specific sequence or secondary structure of the transcripts, with a variety of RNA binding proteins (RBPs), leading to including the 50 and 30-UTR (untranslated region) of the alternations of mRNA stability, splicing, protein stability transcript. In addition to transcripts, proteins can also be and subcellular localization. In addition, lncRNAs may bind subject to post-translational modifications such as phos- to complementary RNA sequences of target genes as post- phorylation, acetylation and ubiquitination. Through these transcriptional regulators. Thus, lncRNAs can impact almost modifications, proteins may change their activity, stability every aspect of gene expression. Here, we will provide a or subcellular localization. few of examples to illustrate how lncRNAs can regulate Thus, RBPs participate in both RNA processing and pro- gene expression at the post-transcriptional level. tein modifications. Especially for hnRNP proteins, they are very important to RNA processing events such as pre-mRNA splicing, mRNA export, localization, translation and stabil- LncRNA-associated ribonucleoprotein (RNP) ity.33 These proteins are often abundantly present in the complexes cells and most of them are resided in the nucleus. Emerging evidence suggests that lncRNAs can directly or indirectly Although lncRNAs are very powerful as master gene regula- participate in these processes by the formation of RNP tors, they do not act alone. Instead, they often work through complexes. Therefore, we will discuss how lncRNAs regu- various partnerships. The most common partnerships are the late mRNA splicing, mRNA stability, protein stability and ribonucleoprotein (RNP) complexes consisting of lncRNAs and protein subcellular localization through RBPs. 8 R.-Z. He et al. Regulation of mRNA splicing cancer.41 Thus, MALAT1 facilitates a pro-metastatic phenotype by promoting alternative RNA processing and Higher eukaryotes utilize alternative splicing
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