Uzun Kodlamayan RNA’lar ve Terapötik Yaklaşımlar
Özet
Genom dizileme teknolojilerindeki gelişmelerle önemi anlaşılan ve 200 nükleotidden uzun olan uzun kodlamayan RNA'lar (lncRNA), protein kodlamayan ancak hücresel süreçlerde kritik düzenleyici rollere sahip moleküllerdir. Genellikle düşük ekspresyon düzeyine ve yüksek doku spesifikliğine sahip olan lncRNA'lar, hücre içi lokalizasyonlarına bağlı olarak işlev görürler. Transkripsiyonel düzeyde kromatin yapısını modifiye ederek, DNA metiltransferazlarla veya transkripsiyon faktörleriyle etkileşerek gen ekspresyonunu aktive eder veya baskılarlar. Post-transkripsiyonel düzeyde ise alternatif splayzing, mRNA stabilitesi ve yıkımı süreçlerine katılırlar, ayrıca miRNA'lar için sünger görevi görerek ceRNA olarak işlev görebilirler. Translasyonel süreçleri ve ubikitinasyon, fosforilasyon, asetilasyon gibi post-translasyonel modifikasyonları da düzenleyen lncRNA'ların anormal ekspresyonları kanser ve otoimmün hastalıklarla yakından ilişkilidir. Hücre hatlarındaki bu etkilerinden dolayı lncRNA'lar; siRNA, ASO, LNA GapmeR, mixmer, aptamer ve CRISPR/Cas9 gibi yöntemlerle post-transkripsiyonel veya genomik düzeyde hedeflenen umut verici terapötik moleküllerdir. Henüz kliniğe girmiş bir lncRNA ilacı olmasa da, devam eden preklinik çalışmalar gelecekteki hastalık tedavileri için büyük potansiyel taşımaktadır.
Long non-coding RNAs (lncRNAs), whose importance has been understood through advancements in genome sequencing technologies and which are longer than 200 nucleotides, are molecules that do not code for proteins but possess critical regulatory roles in cellular processes. Generally having low expression levels and high tissue specificity, lncRNAs function based on their intracellular localization. At the transcriptional level, they activate or repress gene expression by modifying chromatin structure and interacting with DNA methyltransferases or transcription factors. At the post-transcriptional level, they participate in alternative splicing, mRNA stability, and degradation processes, and can also act as ceRNAs by serving as sponges for miRNAs. Regulating translational processes and post-translational modifications such as ubiquitination, phosphorylation, and acetylation, abnormal expressions of lncRNAs are closely associated with cancer and autoimmune diseases. Due to these effects in cell lines, lncRNAs are promising therapeutic targets addressed at post-transcriptional or genomic levels using methods such as siRNA, ASO, LNA GapmeR, mixmers, aptamers, and CRISPR/Cas9. Although no lncRNA-based therapeutic has entered clinical use yet, ongoing preclinical studies hold great potential for future disease treatments.
Referanslar
Zhang L, Peng D, Sood AK, Dang C V. and Zhong X: Shedding Light on the Dark Cancer Genomes: Long Noncoding RNAs as Novel Biomarkers and Potential Therapeutic Targets for Cancer. Mol Cancer Ther 17: 1816–1823, 2018.
Gao N, Li Y, Li J, et al.: Long Non-Coding RNAs: The Regulatory Mechanisms, Research Strategies, and Future Directions in Cancers. Front Oncol 10: 2903, 2020.
Choi SW, Kim HW and Nam JW: The small peptide world in long noncoding RNAs. Brief Bioinform 20: 1853–1864, 2019.
Hartford CCR and Lal A: When Long Noncoding Becomes Protein Coding. Mol Cell Biol 40, 2020.
Chi Y, Wang D, Wang J, Yu W and Yang J: Long Non-Coding RNA in the Pathogenesis of Cancers. Cells 8, 2019.
Miao H, Wang L, Zhan H, et al.: A long noncoding RNA distributed in both nucleus and cytoplasm operates in the PYCARD-regulated apoptosis by coordinating the epigenetic and translational regulation. PLoS Genet 15, 2019.
Hermans-Beijnsberger S, van Bilsen M and Schroen B: Long non-coding RNAs in the failing heart and vasculature. Non-coding RNA Res 3: 118–130, 2018.
Chen Y, Li Z, Chen X and Zhang S: Long non-coding RNAs: From disease code to drug role. Acta Pharm Sin B 11: 340–354, 2021.
Fathi Dizaji B: Strategies to target long non-coding RNAs in cancer treatment: progress and challenges. Egypt J Med Hum Genet 21, 2020.
Balas MM and Johnson AM: Exploring the mechanisms behind long noncoding RNAs and cancer. Non-coding RNA Res 3: 108–117, 2018.
Statello L, Guo CJ, Chen LL and Huarte M: Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol 22: 1, 2021.
Kopp F and Mendell JT: Functional classification and experimental dissection of long noncoding RNAs. Cell 172: 393, 2018.
Yang Y and Li G: Post-translational modifications of PRC2: signals directing its activity. Epigenetics Chromatin 2020 131 13: 1–16, 2020.
Jarroux J, Foretek D, Bertrand C, et al.: HOTAIR lncRNA promotes epithelial-mesenchymal transition by redistributing LSD1 at regulatory chromatin regions. EMBO Rep 22, 2021.
Kondo Y, Shinjo K and Katsushima K: Long non-coding RNAs as an epigenetic regulator in human cancers. Cancer Sci 108: 1927–1933, 2017.
Holdt LM, Hoffmann S, Sass K, et al.: Alu elements in ANRIL non-coding RNA at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks. PLoS Genet 9, 2013.
Yap KL, Li S, Muñoz-Cabello AM, et al.: Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell 38: 662–674, 2010.
Dykes IM and Emanueli C: Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA. Genomics Proteomics Bioinformatics 15: 177, 2017.
Ghafouri-Fard S, Dashti S and Taheri M: The HOTTIP (HOXA transcript at the distal tip) lncRNA: Review of oncogenic roles in human. Biomed Pharmacother 127, 2020.
Fan J, Xing Y, Wen X, et al.: Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis. Genome Biol 16: 1–17, 2015.
Blank-Giwojna A, Postepska-Igielska A and Grummt I: lncRNA KHPS1 Activates a Poised Enhancer by Triplex-Dependent Recruitment of Epigenomic Regulators. Cell Rep 26: 2904-2915.e4, 2019.
Puvvula PK, Desetty RD, Pineau P, Marchio A, Moon A, Dejean A and Bischof O: Long noncoding RNA PANDA and scaffold-attachment-factor SAFA control senescence entry and exit. Nat Commun 5, 2014.
Ng SY, Bogu GK, Soh BS and Stanton LW: The long noncoding RNA RMST interacts with SOX2 to regulate neurogenesis. Mol Cell 51: 349–359, 2013.
Long Y, Wang X, Youmans DT and Cech TR: How do lncRNAs regulate transcription? Sci Adv 3, 2017.
Zhang X, Wang W, Zhu W, Dong J, Cheng Y, Yin Z and Shen F: Mechanisms and Functions of Long Non-Coding RNAs at Multiple Regulatory Levels. Int J Mol Sci 20, 2019.
Giles KE, Woolnough JL and Atwood B: ncRNA function in chromatin organization. Epigenetic Gene Expr Regul: 117–148, 2015.
Qi D, Li J, Que B, et al.: Long non-coding RNA DBCCR1-003 regulate the expression of DBCCR1 via DNMT1 in bladder cancer. Cancer Cell Int 16: 81, 2016.
Chen H, Du G, Song X and Li L: Non-coding Transcripts from Enhancers: New Insights into Enhancer Activity and Gene Expression Regulation. Genomics Proteomics Bioinformatics 15: 201–207, 2017.
Keren H, Lev-Maor G and Ast G: Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet 2010 115 11: 345–355, 2010.
Ouyang J, Zhong Y, Zhang Y, et al.: Long non-coding RNAs are involved in alternative splicing and promote cancer progression. Br J Cancer, 2021.
Tripathi V, Ellis JD, Shen Z, et al.: The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39: 925–938, 2010.
Zhang X, Hamblin MH and Yin KJ: The long noncoding RNA Malat1: Its physiological and pathophysiological functions. RNA Biol 14: 1705, 2017.
Romero-Barrios N, Legascue MF, Benhamed M, Ariel F and Crespi M: Splicing regulation by long noncoding RNAs. Nucleic Acids Res 46: 2169, 2018.
Sebastian-delaCruz M, Gonzalez-Moro I, Olazagoitia-Garmendia A, Castellanos-Rubio A and Santin I: The Role of lncRNAs in Gene Expression Regulation through mRNA Stabilization. Non-Coding RNA 7, 2021.
Faghihi MA, Zhang M, Huang J, et al.: Evidence for natural antisense transcript-mediated inhibition of microRNA function. Genome Biol 11, 2010.
Neve B, Jonckheere N, Vincent A and Van Seuningen I: Epigenetic Regulation by lncRNAs: An Overview Focused on UCA1 in Colorectal Cancer. Cancers (Basel) 10, 2018.
Zhao Y, Liu Y, Lin L, et al.: The lncRNA MACC1-AS1 promotes gastric cancer cell metabolic plasticity via AMPK/Lin28 mediated mRNA stability of MACC1. Mol Cancer 17, 2018.
Li Y, Han X, Feng H and Han J: Long noncoding RNA OIP5-AS1 in cancer. Clin Chim Acta 499: 75–80, 2019.
Priyanka P, Sharma M, Das S and Saxena S: The lncRNA HMS recruits RNA-binding protein HuR to stabilize the 3’-UTR of HOXC10 mRNA. J Biol Chem 297, 2021.
Abdelmohsen K, Panda AC, Kang MJ, et al.: 7SL RNA represses p53 translation by competing with HuR. Nucleic Acids Res 42: 10099–10111, 2014.
Elguindy MM and Mendell JT: NORAD-induced PUMILIO phase separation is required for genome stability. Nature 595: 303, 2021.
Wang X, Zhang J and Wang Y: Long noncoding RNA GAS5-AS1 suppresses growth and metastasis of cervical cancer by increasing GAS5 stability. Am J Transl Res 11: 4909, 2019.
Zhang L, Yang Z, Trottier J, Barbier O and Wang L: Long noncoding RNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate shp mRNA decay. Hepatology 65: 604–615, 2017.
Marchese FP, Raimondi I and Huarte M: The multidimensional mechanisms of long noncoding RNA function. Genome Biol 18, 2017.
Ghafouri-Fard S, Khoshbakht T, Taheri M and Shojaei S: A Review on the Role of Small Nucleolar RNA Host Gene 6 Long Non-coding RNAs in the Carcinogenic Processes. Front cell Dev Biol 9, 2021.
Sun J, Wang X, Fu C, Wang X, Zou J, Hua H and Bi Z: Long noncoding RNA FGFR3-AS1 promotes osteosarcoma growth through regulating its natural antisense transcript FGFR3. Mol Biol Rep 43: 427–436, 2016.
Tan YT, Lin JF, Li T, Li JJ, Xu RH and Ju HQ: LncRNA-mediated posttranslational modifications and reprogramming of energy metabolism in cancer. Cancer Commun (London, England) 41: 109–120, 2021.
Qin G, Tu X, Li H, et al.: Long Noncoding RNA p53-Stabilizing and Activating RNA Promotes p53 Signaling by Inhibiting Heterogeneous Nuclear Ribonucleoprotein K deSUMOylation and Suppresses Hepatocellular Carcinoma. Hepatology 71: 112–129, 2020.
Su T, Wang T, Zhang N, Shen Y, Li W, Xing H and Yang M: Long non-coding RNAs in gastrointestinal cancers: Implications for protein phosphorylation. Biochem Pharmacol 197, 2022.
Wang P, Xue Y, Han Y, et al.: The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation. Science 344: 310–313, 2014.
Chen R, Liu Y, Zhuang H, et al.: Quantitative proteomics reveals that long non-coding RNA MALAT1 interacts with DBC1 to regulate p53 acetylation. Nucleic Acids Res 45: 9947–9959, 2017.
Winkle M, El-Daly SM, Fabbri M and Calin GA: Noncoding RNA therapeutics - challenges and potential solutions. Nat Rev Drug Discov 20: 629–651, 2021.
Arun G, Diermeier SD and Spector DL: Therapeutic Targeting of Long Non-Coding RNAs in Cancer. Trends Mol Med 24: 257–277, 2018.
Parasramka MA, Maji S, Matsuda A, Yan IK and Patel T: Long non-coding RNAs as novel targets for therapy in hepatocellular carcinoma. Pharmacol Ther 161: 67–78, 2016.
Zhang J, Li Q, Xue B and He R: MALAT1 inhibits the Wnt/β-catenin signaling pathway in colon cancer cells and affects cell proliferation and apoptosis. Bosn J Basic Med Sci 20: 357, 2020.
Montes M and Arnes L: Expert Opinion on Therapeutic Targets ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iett20 lncRNAs: potential therapeutic targets and biomarkers for pancreatic cancer? lncRNAs: potential therapeutic targets and biomarkers for pa., 2021.
Yoo BH, Bochkareva E, Bochakarev A, Mou TC and Gray DM: 2’-O-methyl-modified phosphorothioate antisense oligonucleotides have reduced non-specific effects in vitro. Nucleic Acids Res 32: 2008–2016, 2004.
Ishige T, Itoga S and Matsushita K: Locked Nucleic Acid Technology for Highly Sensitive Detection of Somatic Mutations in Cancer. Adv Clin Chem 83: 53–72, 2018.
Renganathan A and Felley-Bosco E: Long Noncoding RNAs in Cancer and Therapeutic Potential. Adv Exp Med Biol 1008: 199–222, 2017.
Xiao X, Li H, Zhao L, Zhang Y and Liu Z: Oligonucleotide aptamers: Recent advances in their screening, molecular conformation and therapeutic applications. Biomed Pharmacother 143, 2021.
Wang Y-L, Chang L-C, Chen K-B and Wang S-C: Aptamer-guided targeting of the intracellular long-noncoding RNA HOTAIR. Am J Cancer Res 11: 945, 2021.
Rosenlund IA, Calin GA, Dragomir MP and Knutsen E: CRISPR/Cas9 to Silence Long Non-Coding RNAs. Methods Mol Biol 2348: 175–187, 2021.
Zare K, Shademan M, Ghahramani Seno MM and Dehghani H: CRISPR/Cas9 Knockout Strategies to Ablate CCAT1 lncRNA Gene in Cancer Cells. Biol Proced Online 20, 2018.
