Skip to main content

Advertisement

SpringerLink
Log in

The growth arrest-specific transcript 5 (GAS5): a pivotal tumor suppressor long noncoding RNA in human cancers

  • Review
  • Published:
Tumor Biology

Abstract

Long noncoding RNAs (lncRNAs), which refer to a group of RNAs with length more than 200 nucleotides and limited protein-coding potential, play a widespread role in regulating biological processes, such as cell differentiation, proliferation, apoptosis, and migration. LncRNAs are dysregulated in multiple cancers, playing an either oncogenic or tumor-suppressive role. LncRNA GAS5 is a recently identified tumor suppressor involved in several cancers, like breast cancer, prostate cancer, lung cancer, and colorectal cancer. The low-expression pattern confers tumor cells elevated capacity of proliferation and predicts poorer prognosis. Existing studies mirror that lncRNA GAS5 promises to be a novel diagnostic biomarker, therapy target, as well as prognostic biomarker. In this review, we will summarize the current knowledge about this vital lncRNA, from its discovery, characteristics, and biological function to molecular mechanism in various neoplasms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

GAS5:

Growth arrest-specific transcript 5

lncRNAs:

Long noncoding RNAs

miRNAs:

MicroRNAs

snoRNA:

Small nucleolar RNA

m-TOR:

Mammalian target of rapamycin

NMD:

Nonsense-mediated decay

GR:

Glucocorticoid receptor

GRE:

Glucocorticoid response element

DBD:

DNA-binding domain

PLXN C1:

Plexin C1

YBX1:

Y-box binding protein 1

ADT:

Androgen deprivation therapy

CRPC:

Castrate-resistant prostate cancer

NSCLC:

Nonsmall-cell lung cancer

5-aza-CdR:

5-Aza-2-deoxy-cytidine

EGFR-TKIs:

Epidermal growth factor receptor tyrosine kinase inhibitors

IGF-1R:

Insulin-like growth factor 1 receptor

MPM:

Malignant pleural mesothelioma

CDK6:

Cyclin-dependent kinase 6

RCC:

Renal cell carcinoma

HOTAIR:

Hox transcript antisense intergenic RNA

PRC2:

Polycomb repressive complex 2

LSD1:

Lysine-specific demethylase 1

References

  1. Booton R, Lindsay MA. Emerging role of MicroRNAs and long noncoding RNAs in respiratory disease. Chest. 2014;146(1):193–204.

    Article  CAS  PubMed  Google Scholar 

  2. Consortium TEP. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57–74.

    Article  Google Scholar 

  3. Nagano T, Fraser P. No-nonsense functions for long noncoding RNAs. Cell. 2011;145(2):178–81.

    Article  CAS  PubMed  Google Scholar 

  4. Hammond SM. An overview of microRNAs. Adv Drug Deliv Rev. 2015;87:3–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pritchard CC, Cheng HH, Tewari M. MicroRNA profiling: approaches and considerations. Nat Rev Genet. 2012;13(5):358–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, et al. The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression. Genome Res. 2012;22(9):1775–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wapinski O, Chang HY. Long noncoding RNAs and human disease. Trends Cell Biol. 2011;21(6):354–61.

    Article  CAS  PubMed  Google Scholar 

  8. Gibb EA, Brown CJ, Lam WL. The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 2011;10:38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shi X, Sun M, Wu Y, Yao Y, Liu H, Wu G, et al. Post-transcriptional regulation of long noncoding RNAs in cancer. Tumour Biol. 2015;36(2):503–13.

    Article  CAS  PubMed  Google Scholar 

  10. Sun M, Jin FY, Xia R, Kong R, Li JH, Xu TP, et al. Decreased expression of long noncoding RNA GAS5 indicates a poor prognosis and promotes cell proliferation in gastric cancer. BMC Cancer. 2014;14:319.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Shi X, Sun M, Liu H, Yao Y, Kong R, Chen F, et al. A critical role for the long non-coding RNA GAS5 in proliferation and apoptosis in non-small-cell lung cancer. Mol Carcinog. 2015;54 Suppl 1:E1–E12.

    Article  CAS  PubMed  Google Scholar 

  12. Yacqub-Usman K, Pickard MR, Williams GT. Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells. Prostate. 2015;75(7):693–705.

    Article  CAS  PubMed  Google Scholar 

  13. Stahel RA, Weder W, Felip E. Malignant pleural mesothelioma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20 Suppl 4:73–5.

    PubMed  Google Scholar 

  14. Schneider C, King RM, Philipson L. Genes specifically expressed at growth arrest of mammalian cells. Cell. 1988;54:787–93.

    Article  CAS  PubMed  Google Scholar 

  15. SMITH CM, STEITZ JA. Classification of gas5 as a multi-small-nucleolar-RNA (snoRNA) host gene and a member of the 5′terminal oligopyrimidine gene family reveals common features of snoRNA host genes. Mol Cell Biol. 1998;18(12):6897–909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Williams GT, Farzaneh F. Are snoRNAs and snoRNA host genes new players in cancer? Nat Rev Cancer. 2012;12(2):84–8.

    CAS  PubMed  Google Scholar 

  17. COCCIA EM, Cicala C, Charlesworth A, Ciccarelli C, Rossi GB, Philipson L, et al. Regulation and expression of a growth arrest-specific gene (gas5) during growth, differentiation, and development. Mol Cell Biol. 1992;12(8):3514–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mourtada-Maarabouni M, Hasan AM, Farzaneh F, Williams GT. Inhibition of human T-cell proliferation by mammalian target of rapamycin (mTOR) antagonists requires noncoding RNA growth-arrest-specific transcript 5 (GAS5). Mol Pharmaco. 2010;78(1):19–28.

    Article  CAS  Google Scholar 

  19. Tani H, Torimura M, Akimitsu N. The RNA degradation pathway regulates the function of GAS5 a non-coding RNA in mammalian cells. PLoS One. 2013;8(1):e55684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Meyuhas O. Synthesis of the translational apparatus is regulated at the translational level. Eur J Biochem. 2000;267(21):6321–30.

    Article  CAS  PubMed  Google Scholar 

  21. Tani H, Imamachi N, Salam KA, Mizutani R, Ijiri K, Irie T, et al. Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability. RNA Biol. 2012;9(11):1370–9.

  22. Imamachi N. Up-frameshift protein 1 (UPF1): multitalented entertainer in RNA decay. Drug Discov Ther. 2012;6(2):55–61.

    CAS  PubMed  Google Scholar 

  23. Mendell JT, Sharifi NA, Meyers JL, Martinez-Murillo F, Dietz HC. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nat Genet. 2004;36(10):1073–8.

    Article  CAS  PubMed  Google Scholar 

  24. Isken O, Maquat LE. Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function. Genes Dev. 2007;21(15):1833–56.

    Article  CAS  PubMed  Google Scholar 

  25. Mourtada-Maarabouni M, Hedge VL, Kirkham L, Farzaneh F, Williams GT. Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5). J Cell Sci. 2008;121(Pt 7):939–46.

    Article  CAS  PubMed  Google Scholar 

  26. Nakamura Y, Takahashi N, Kakegawa E, Yoshida K, Ito Y, Kayano H, et al. The GAS5 (growth arrest-specific transcript 5) gene fuses to BCL6 as a result of t(1;3)(q25;q27) in a patient with B-cell lymphoma. Cancer Genet Cytogenet. 2008;182(2):144–9.

    Article  CAS  PubMed  Google Scholar 

  27. Yin D, He X, Zhang E, Kong R, De W, Zhang Z. Long noncoding RNA GAS5 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer. Med Oncol. 2014;31(11):253.

    Article  PubMed  Google Scholar 

  28. Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT. GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene. 2009;28(2):195–208.

    Article  CAS  PubMed  Google Scholar 

  29. Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP. Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal. 2010;3(107):ra8.

    PubMed  PubMed Central  Google Scholar 

  30. Zhang Z, Zhu Z, Watabe K, Zhang X, Bai C, Xu M, et al. Negative regulation of lncRNA GAS5 by miR-21. Cell Death Differ. 2013;20(11):1558–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhao X, Wang P, Liu J, Zheng J, Liu Y, Chen J, et al. Gas5 exerts tumor-suppressive functions in human glioma cells by targeting miR-222. Mol Ther. 2015. doi:10.1038/mt.2015.170

  32. Hu G, Lou Z, Gupta M. The long non-coding RNA GAS5 cooperates with the eukaryotic translation initiation factor 4E to regulate c-Myc translation. PLoS One. 2014;9(9):e107016.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Liu Y, Zhao J, Zhang W, Gan J, Hu C, Huang G, et al. LncRNA GAS5 enhances G1 cell cycle arrest via binding to YBX1 to regulate p21 expression in stomach cancer. Sci Rep. 2015;5:10159.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hajjari M, Salavaty A. HOTAIR: an oncogenic long non-coding RNA in different cancers. Cancer Biol Med. 2015;12(1):1–9.

    PubMed  PubMed Central  Google Scholar 

  35. Wu Y, Zhang L, Wang Y, Li H, Ren X, Wei F, et al. Long noncoding RNA HOTAIR involvement in cancer. Tumour Biol. 2014;35(10):9531–8.

    Article  CAS  PubMed  Google Scholar 

  36. Yan L, Zhou J, Gao Y, Ghazal S, Lu L, Bellone S, et al. Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation. Oncogene. 2014;34(23):3076–84.

    Article  PubMed  Google Scholar 

  37. Li S, Wang Q, Qiang Q, Shan H, Shi M, Chen B, et al. Sp1-mediated transcriptional regulation of MALAT1 plays a critical role in tumor. J Cancer Res Clin Oncol. 2015;141(11):1909–20.

    Article  CAS  PubMed  Google Scholar 

  38. Pickard MR, Williams GT. Regulation of apoptosis by long non-coding RNA GAS5 in breast cancer cells: implications for chemotherapy. Breast Cancer Res Treat. 2014;145(2):359–70.

    Article  CAS  PubMed  Google Scholar 

  39. Tamburrino L, Salvianti F, Marchiani S, Pinzani P, Nesi G, Serni S, et al. Androgen receptor (AR) expression in prostate cancer and progression of the tumor: Lessons from cell lines, animal models and human specimens. Steroids. 2012;77(10):996–1001.

    Article  CAS  PubMed  Google Scholar 

  40. Pickard MR, Mourtada-Maarabouni M, Williams GT. Long non-coding RNA GAS5 regulates apoptosis in prostate cancer cell lines. Biochim Biophys Acta. 2013;1832(10):1613–23.

    Article  CAS  PubMed  Google Scholar 

  41. Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. 2015;4(1):36–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Perez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, et al. Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer. J Clin Oncol. 2004;22(16):3238–47.

    Article  CAS  PubMed  Google Scholar 

  43. Takahashi K, Yan I, Haga H, Patel T. Long noncoding RNA in liver diseases. Hepatology. 2014;60(2):744–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Svoboda M, Slyskova J, Schneiderova M, Makovicky P, Bielik L, Levy M, et al. HOTAIR long non-coding RNA is a negative prognostic factor not only in primary tumors, but also in the blood of colorectal cancer patients. Carcinogenesis. 2014;35(7):1510–5.

    Article  CAS  PubMed  Google Scholar 

  45. Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, et al. A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25(5):666–81.

  46. Ling H, Vincent K, Pichler M, Fodde R, Berindan-Neagoe I, Slack FJ, et al. Junk DNA and the long non-coding RNA twist in cancer genetics. Oncogene. 2015;34(39):5003–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tsang WP, Wong TW, Cheung AH, Co CN, Kwok TT. Induction of drug resistance and transformation in human cancer cells by the noncoding RNA CUDR. RNA. 2007;13(6):890–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jiang M, Huang O, Xie Z, Wu S, Zhang X, Shen A, et al. A novel long non-coding RNA-ARA: adriamycin resistance-associated. Biochem Pharmacol. 2014;87(2):254–83.

    Article  CAS  PubMed  Google Scholar 

  49. Yang Y, Li H, Hou S, Hu B, Liu J, Wang J. The noncoding RNA expression profile and the effect of lncRNA AK126698 on cisplatin resistance in non-small-cell lung cancer cell. PLoS One. 2013;8(5):e65309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cheng N, Li X, Zhao C, Ren S, Chen X, Cai W, et al. Microarray expression profile of long non-coding RNAs in EGFR-TKIs resistance of human non-small cell lung cancer. Oncol Rep. 2015;33(2):833–9.

    CAS  PubMed  Google Scholar 

  51. Dong S, Qu X, Li W, Zhong X, Li P, Yang S, et al. The long non-coding RNA, GAS5, enhances gefitinib-induced cell death in innate EGFR tyrosine kinase inhibitor-resistant lung adenocarcinoma cells with wide-type EGFR via downregulation of the IGF-1R expression. J Hematol Oncol. 2015;8(1):43.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Wright CM, Kirschner MB, Cheng YY, O’Byrne KJ, Gray SG, Schelch K, et al. Long non coding RNAs (lncRNAs) are dysregulated in malignant pleural mesothelioma (MPM). PLoS One. 2013;8:e70940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Renganathan A, Kresoja-Rakic J, Echeverry N, Ziltener G, Vrugt B, Opitz I, et al. GAS5 long non-coding RNA in malignant pleural mesothelioma. Mol Cancer. 2014;13:119.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Lu X, Fang Y, Wang Z, Xie J, Zhan Q, Deng X, et al. Downregulation of gas5 increases pancreatic cancer cell proliferation by regulating CDK6. Cell Tissue Res. 2013;354(3):891–6.

    Article  CAS  PubMed  Google Scholar 

  55. Liu Z, Wang W, Jiang J, Bao E, Xu D, Zeng Y, et al. Downregulation of GAS5 promotes bladder cancer cell proliferation, partly by regulating CDK6. PLoS ONE. 2013;8(9):e73991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Qiao HP, Gao WS, Huo JX, Yang ZS. Long non-coding RNA GAS5 functions as a tumor suppressor in renal cell carcinoma. Asian Pac J Cancer Prev. 2013;14(2):1077–82.

    Article  PubMed  Google Scholar 

  57. Tu ZQ, Li RJ, Mei JZ, Li XH. Down-regulation of long non-coding RNA GAS5 is associated with the prognosis of hepatocellular carcinoma. Int J Clin Exp Pathol. 2014;7(7):4303–9.

    PubMed  PubMed Central  Google Scholar 

  58. Cao S, Liu W, Li F, Zhao W, Qin C. Decreased expression of lncRNA GAS5 predicts a poor prognosis in cervical cancer. Int J Clin Exp Pathol. 2014;7(10):6776–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Dufour M, Dormond-Meuwly A, Demartines N, Dormond O. Targeting the mammalian target of rapamycin (mTOR) in cancer therapy: lessons from past and future perspectives. Cancers (Basel). 2011;3(2):2478–500.

    Article  CAS  Google Scholar 

  60. Zaytseva YY, Valentino JD, Gulhati P, Evers BM. mTOR inhibitors in cancer therapy. Cancer Lett. 2012;319(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  61. Gezer U, Özgür E, Cetinkaya M, Isin M, Dalay N. Long non-coding RNAs with low expression levels in cells are enriched in secreted exosomes. Cell Biol Int. 2014;38(9):1076–9.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Natural Science Foundation of Jiangsu Province (no. BK2011658), Clinical Science and Technology Project of Jiangsu Province (no. BL2013026), and the National Natural Science Foundation of China (no. 81401903). We apologize to all researchers whose relevant contributions were not cited due to space limitations.

Author information

Authors and Affiliations

  1. Department of Respiratory Medicine, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China

    Chenhui Ma, Qingqing Zhu, Qian Li, Yanwen Yao & Yong Song

  2. Department of Respiratory Medicine, Jinling Hospital, Southern Medical University (Guangzhou), Nanjing, China

    Yafang Liu

  3. Department of Respiratory Medicine, Huzhou Central Hospital, Huzhou, China

    Xuefei Shi

Authors
  1. Chenhui Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuefei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qingqing Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yafang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yanwen Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yong Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong Song.

Ethics declarations

Conflicts of interest

None

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, C., Shi, X., Zhu, Q. et al. The growth arrest-specific transcript 5 (GAS5): a pivotal tumor suppressor long noncoding RNA in human cancers. Tumor Biol. 37, 1437–1444 (2016). https://doi.org/10.1007/s13277-015-4521-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4521-9

Keywords

Search

Navigation