Abstract
Lung adenocarcinomas are more common in non-smoking males and females. In this study, we investigated the function of long non-coding RNA RMRP in lung adenocarcinoma and further explore the regulatory role of ALKBH5 in lncRNA methylation. The results showed lncRNA RMRP expression was significantly enhanced in lung adenocarcinoma tissues, and is positively correlated with poor prognosis. RMRP knockdown in lung adenocarcinoma cell lines suppressed cell proliferation, migration and invasion, and promoted cell apoptosis. In addition, ALKBH5 upregulated RMRP expression via demethylation, and ALKBH5 knockdown inhibited the tumorigenesis of lung adenocarcinoma in vitro and vivo. Given these clear patterns, suppressing RMRP through ALKBH5 manipulation may represent a promising therapeutic target for lung adenocarcinoma.
Similar content being viewed by others
References
Aik W, Scotti JS, Choi H, Gong L, Demetriades M, Schofield CJ, McDonough MA (2014) Structure of human RNA N(6)-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation. Nucleic Acids Res 42:4741–4754
Boccaletto P, Machnicka MA, Purta E, Piatkowski P, Baginski B, Wirecki TK, de Crecy-Lagard V, Ross R, Limbach PA, Kotter A, Helm M, Bujnicki JM (2018) MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res 46:D303–D307
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin 68:394–424
Calvayrac O, Pradines A, Pons E, Mazieres J, Guibert N (2017) Molecular biomarkers for lung adenocarcinoma. Eur Respir J 49:1601734
Chen S, Zhou L, Wang Y (2020) ALKBH5-mediated m(6)A demethylation of lncRNA PVT1 plays an oncogenic role in osteosarcoma. Cancer Cell Int 20:34
Deng X, Su R, Weng H, Huang H, Li Z, Chen J (2018) RNA N(6)-methyladenosine modification in cancers: current status and perspectives. Cell Res 28:507–517
Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–1075
Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, Hershkovitz V, Peer E, Mor N, Manor YS, Ben-Haim MS, Eyal E, Yunger S, Pinto Y, Jaitin DA, Viukov S, Rais Y, Krupalnik V, Chomsky E, Zerbib M, Maza I, Rechavi Y, Massarwa R, Hanna S, Amit I, Levanon EY, Amariglio N, Stern-Ginossar N, Novershtern N, Rechavi G, Hanna JH (2015) Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347:1002–1006
He Y, Hu H, Wang Y, Yuan H, Lu Z, Wu P, Liu D, Tian L, Yin J, Jiang K, Miao Y (2018) ALKBH5 inhibits pancreatic cancer motility by decreasing long non-coding RNA KCNK15-AS1 methylation. Cell Physiol Biochem : Int J Exp Cell Physiol, Biochem, Pharmacol 48:838–846
Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, Cho J, Suh J, Capelletti M, Sivachenko A, Sougnez C, Auclair D, Lawrence MS, Stojanov P, Cibulskis K, Choi K, de Waal L, Sharifnia T, Brooks A, Greulich H, Banerji S, Zander T, Seidel D, Leenders F, Ansen S, Ludwig C, Engel-Riedel W, Stoelben E, Wolf J, Goparju C, Thompson K, Winckler W, Kwiatkowski D, Johnson BE, Janne PA, Miller VA, Pao W, Travis WD, Pass HI, Gabriel SB, Lander ES, Thomas RK, Garraway LA, Getz G, Meyerson M (2012) Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150:1107–1120
Lan Q, Liu PY, Haase J, Bell JL, Huttelmaier S, Liu T (2019) The critical role of RNA m(6)A methylation in cancer. Cancer Res 79:1285–1292
Lee M, Kim B, Kim VN (2014) Emerging roles of RNA modification: m(6)A and U-tail. Cell 158:980–987
Ma T, Hu Y, Guo Y, Yan B (2019) Tumor-promoting activity of long noncoding RNA LINC00466 in lung adenocarcinoma via miR-144-regulated HOXA10 axis. Am J Pathol 189:2154–2170
Mattick JS, Rinn JL (2015) Discovery and annotation of long noncoding RNAs. Nat Struct Mol Biol 22:5–7
Matyi S, Jackson J, Garrett K, Deepa SS, Unnikrishnan A (2018) The effect of different levels of dietary restriction on glucose homeostasis and metabolic memory. Geroscience 40:139–149
Mercer TR, Mattick JS (2013) Structure and function of long noncoding RNAs in epigenetic regulation. Nat Struct Mol Biol 20:300–307
Meyer KD, Jaffrey SR (2014) The dynamic epitranscriptome: N6-methyladenosine and gene expression control. Nat Rev Mol Cell Biol 15:313–326
Pan J, Zhang D, Zhang J, Qin P, Wang J (2019) LncRNA RMRP silence curbs neonatal neuroblastoma progression by regulating microRNA-206/tachykinin-1 receptor axis via inactivating extracellular signal-regulated kinases. Cancer Biol Ther 20:653–665
Ringner M, Jonsson G, Staaf J (2016) Prognostic and chemotherapy predictive value of gene-expression phenotypes in primary lung adenocarcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res 22:218–229
Rogler LE, Kosmyna B, Moskowitz D, Bebawee R, Rahimzadeh J, Kutchko K, Laederach A, Notarangelo LD, Giliani S, Bouhassira E, Frenette P, Roy-Chowdhury J, Rogler CE (2014) Small RNAs derived from lncRNA RNase MRP have gene-silencing activity relevant to human cartilage-hair hypoplasia. Hum Mol Genet 23:368–382
Roundtree IA, Evans ME, Pan T, He C (2017) Dynamic RNA modifications in gene expression regulation. Cell 169:1187–1200
Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA: Cancer J Clin 68:7–30
Song H, Sun W, Ye G, Ding X, Liu Z, Zhang S, Xia T, Xiao B, Xi Y, Guo J (2013) Long non-coding RNA expression profile in human gastric cancer and its clinical significances. J Transl Med 11:225
Su C, Shi K, Cheng X, Han Y, Li Y, Yu D, Liu Z (2018) Long noncoding RNA LINC00472 inhibits proliferation and promotes apoptosis of lung adenocarcinoma cells via regulating miR-24-3p/DEDD. Technol Cancer Res Treat 17:1533033818790490
Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43:904–914
Wang J, Xiao T, Zhao M (2019) MicroRNA-675 directly targets MAPK1 to suppress the oncogenicity of papillary thyroid cancer and is sponged by long non-coding RNA RMRP. OncoTargets Ther 12:7307–7321
Wei J, Yan Y, Chen X, Qian L, Zeng S, Li Z, Dai S, Gong Z, Xu Z (2019) The roles of plant-derived triptolide on non-small cell lung cancer. Oncol Res 27:849–858
Yan Y, Chen X, Wang X, Zhao Z, Hu W, Zeng S, Wei J, Yang X, Qian L, Zhou S, Sun L, Gong Z, Xu Z (2019a) The effects and the mechanisms of autophagy on the cancer-associated fibroblasts in cancer. J Exp Clin Cancer Res 38:171
Yan Y, Xu Z, Chen X, Wang X, Zeng S, Zhao Z, Qian L, Li Z, Wei J, Huo L, Li X, Gong Z, Sun L (2019b) Novel function of lncRNA ADAMTS9-AS2 in promoting temozolomide resistance in glioblastoma via upregulating the FUS/MDM2 ubiquitination Axis. Front Cell Dev Biol 7:217
Yang M, Ke H, Zhou W (2020) LncRNA RMRP promotes cell proliferation and invasion through miR-613/NFAT5 axis in non-small cell lung cancer. OncoTargets Ther 13:8941–8950
Zhang J, Guo S, Piao HY, Wang Y, Wu Y, Meng XY, Yang D, Zheng ZC, Zhao Y (2019) ALKBH5 promotes invasion and metastasis of gastric cancer by decreasing methylation of the lncRNA NEAT1. J Physiol Biochem 75:379–389
Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vagbo CB, Shi Y, Wang WL, Song SH, Lu Z, Bosmans RP, Dai Q, Hao YJ, Yang X, Zhao WM, Tong WM, Wang XJ, Bogdan F, Furu K, Fu Y, Jia G, Zhao X, Liu J, Krokan HE, Klungland A, Yang YG, He C (2013) ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 49:18–29
Zhou J, Xiao H, Yang X, Tian H, Xu Z, Zhong Y, Ma L, Zhang W, Qiao G, Liang J (2018) Long noncoding RNA CASC9.5 promotes the proliferation and metastasis of lung adenocarcinoma. Sci Rep. https://doi.org/10.1038/s41598-017-18280-3
Zhou N, He Z, Tang H, Jiang B, Cheng W (2019) LncRNA RMRP/miR-613 axis is associated with poor prognosis and enhances the tumorigenesis of hepatocellular carcinoma by impacting oncogenic phenotypes. Am J Transl Res 11:2801–2815
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors declare no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Yu, H., Zhang, Z. ALKBH5-mediated m6A demethylation of lncRNA RMRP plays an oncogenic role in lung adenocarcinoma. Mamm Genome 32, 195–203 (2021). https://doi.org/10.1007/s00335-021-09872-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-021-09872-6