Abstract
Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in cancer, however, posttranscriptional regulation such as N6-methyladenosine (m6A) of IGF1R remains unclear. Here, we reveal a role for a lncRNA Downregulated RNA in Cancer (DRAIC) suppress tumor growth and metastasis in clear cell Renal Carcinoma (ccRCC). Mechanistically, DRAIC physically interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and enhances its protein stability by blocking E3 ligase F-box protein 11 (FBXO11)-mediated ubiquitination and proteasome-dependent degradation. Subsequently, hnRNPA2B1 destabilizes m6A modified-IGF1R, leading to inhibition of ccRCC progression. Moreover, four m6A modification sites are identified to be responsible for the mRNA degradation of IGF1R. Collectively, our findings reveal that DRAIC/hnRNPA2B1 axis regulates IGF1R mRNA stability in an m6A-dependent manner and highlights an important mechanism of IGF1R fate. These findings shed light on DRAIC/hnRNPA2B1/FBXO11/IGF1R axis as potential therapeutic targets in ccRCC and build a link of molecular fate between m6A-modified RNA and ubiquitin-modified protein.
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Data availability
RNA-seq data of FPKM levels of LUSC, LUAD, ccRCC and ACC, were retrieved from TCGA. hnRNPA2B1 and IGF1R expression data and clinical data were downloaded from TCGA Pan-Cancer project. hnRNPA2B1 eCLIP-seq data (GSE86464) was obtained from the public database GEO; RNA-seq data of DRAIC and hnRNPA2B1 have been deposited in the GEO (GSE244891); M6A-seq data have been deposited in the GEO (GSE262500). The authors declare that the data supporting the findings of this study are available within the manuscript. No restriction on data availability applies. All other data supporting the findings of this study are available from the corresponding author upon reasonable request.
References
Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007;28:20–47.
Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM. The type 1 insulin-like growth factor receptor pathway. Clin Cancer Res 2008;14:6364–70.
Maki RG. Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer. J Clin Oncol. 2010;28:4985–95.
Werner H, Karnieli E, Rauscher FJ, LeRoith D. Wild-type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene. Proc Natl Acad Sci USA. 1996;93:8318–23.
Titone R, Zhu M, Robertson DM. Mutual regulation between IGF-1R and IGFBP-3 in human corneal epithelial cells. J Cell Physiol. 2019;234:1426–41.
Jiang R, Wang M, Shen X, Huang S, Han J, Li L, et al. SUMO1 modification of IGF-1R combining with SNAI2 inhibited osteogenic differentiation of PDLSCs stimulated by high glucose. Stem Cell Res Ther 2021;12:543.
Frye M, Harada BT, Behm M, He C. RNA modifications modulate gene expression during development. Science. 2018;361:1346–9.
Pan Y, Gu Y, Liu T, Zhang Q, Yang F, Duan L, et al. Epitranscriptic regulation of HRAS by N(6)-methyladenosine drives tumor progression. Proc Natl Acad Sci USA. 2023;120:e2302291120.
Gu Y, Niu S, Wang Y, Duan L, Pan Y, Tong Z, et al. DMDRMR-Mediated Regulation of m(6)A-Modified CDK4 by m(6)A Reader IGF2BP3 Drives ccRCC Progression. Cancer Res. 2021;81:923–34.
Wang X, Feng J, Xue Y, Guan Z, Zhang D, Liu Z, et al. Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex. Nature. 2016;534:575–8.
Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7:885–7.
Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49:18–29.
Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161:1388–99.
Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20:285–95.
Alarcón CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 Is a Mediator of m(6)A-dependent nuclear RNA processing events. Cell. 2015;162:1299–308.
Zhang Z, Lu YX, Liu F, Sang L, Shi C, Xie S, et al. lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1. Proc Natl Acad Sci USA. 2023;120:e2206694120.
Yang X, Wen Y, Liu S, Duan L, Liu T, Tong Z, et al. LCDR regulates the integrity of lysosomal membrane by hnRNP K-stabilized LAPTM5 transcript and promotes cell survival. Proc Natl Acad Sci USA. 2022;119:e2110428119.
Sakurai K, Reon BJ, Anaya J, Dutta A. The lncRNA DRAIC/PCAT29 locus constitutes a tumor-suppressive nexus. Mol Cancer Res. 2015;13:828–38.
Zeng Q, Saghafinia S, Chryplewicz A, Fournier N, Christe L, Xie YQ, et al. Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion. Science. 2022;378:eabl7207.
Marchese FP, Raimondi I, Huarte M. The multidimensional mechanisms of long noncoding RNA function. Genome Biol. 2017;18:206.
Huelga SC, Vu AQ, Arnold JD, Liang TY, Liu PP, Yan BY, et al. Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins. Cell Rep. 2012;1:167–78.
Hofacker IL. Vienna RNA secondary structure server. Nucleic Acids Res. 2003;31:3429–31.
Wu B, Su S, Patil DP, Liu H, Gan J, Jaffrey SR, et al. Molecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1. Nat Commun. 2018;9:420.
Zhang H, Xia P, Yang Z, Liu J, Zhu Y, Huang Z, et al. Cullin-associated and neddylation-dissociated 1 regulate reprogramming of lipid metabolism through SKP1-Cullin-1-F-box(FBXO11)-mediated heterogeneous nuclear ribonucleoprotein A2/B1 ubiquitination and promote hepatocellular carcinoma. Clin Transl Med. 2023;13:e1443.
Martinez FJ, Pratt GA, Van Nostrand EL, Batra R, Huelga SC, Kapeli K, et al. Protein-RNA networks regulated by normal and ALS-Associated Mutant HNRNPA2B1 in the nervous system. Neuron. 2016;92:780��95.
Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170:605–35.
Carboni JM, Wittman M, Yang Z, Lee F, Greer A, Hurlburt W, et al. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther. 2009;8:3341–9.
Wu Q, Tian AL, Kroemer G, Kepp O. Autophagy induction by IGF1R inhibition with picropodophyllin and linsitinib. Autophagy. 2021;17:2046–7.
Gao S, Bajrami I, Verrill C, Kigozi A, Ouaret D, Aleksic T, et al. Dsh homolog DVL3 mediates resistance to IGFIR inhibition by regulating IGF-RAS signaling. Cancer Res. 2014;74:5866–77.
Harper JE, Miceli SM, Roberts RJ, Manley JL. Sequence specificity of the human mRNA N6-adenosine methylase in vitro. Nucleic Acids Res. 1990;18:5735–41.
Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485:201–6.
Roberts JT, Porman AM, Johnson AM. Identification of m(6)A residues at single-nucleotide resolution using eCLIP and an accessible custom analysis pipeline. RNA (N. Y, NY). 2021;27:527–41.
Hu L, Liu S, Peng Y, Ge R, Su R, Senevirathne C, et al. m(6)A RNA modifications are measured at single-base resolution across the mammalian transcriptome. Nat Biotechnol. 2022;40:1210–9.
Ke S, Pandya-Jones A, Saito Y, Fak JJ, Vågbø CB, Geula S, et al. m(6)A mRNA modifications are deposited in nascent pre-mRNA and are not required for splicing but do specify cytoplasmic turnover. Genes Dev. 2017;31:990–1006.
Li J, Chen Z, Chen F, Xie G, Ling Y, Peng Y, et al. Targeted mRNA demethylation using an engineered dCas13b-ALKBH5 fusion protein. Nucleic Acids Res. 2020;48:5684–94.
Xiao Y, Wang Y, Tang Q, Wei L, Zhang X, Jia G. An Elongation- and Ligation-Based qPCR Amplification Method for the Radiolabeling-Free Detection of Locus-Specific N(6) -Methyladenosine Modification. Angew Chem (Int ed Engl). 2018;57:15995–6000.
Kopp F, Mendell JT. Functional Classification and Experimental Dissection of Long Noncoding RNAs. Cell. 2018;172:393–407.
Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136:629–41.
Zhu Y, Liu X, Wang Y, Pan Y, Han X, Peng B, et al. DMDRMR promotes angiogenesis via antagonizing DAB2IP in clear cell renal cell carcinoma. Cell Death Dis. 2022;13:456.
Tiessen I, Abildgaard MH, Lubas M, Gylling HM, Steinhauer C, Pietras EJ, et al. A high-throughput screen identifies the long non-coding RNA DRAIC as a regulator of autophagy. Oncogene. 2019;38:5127–41.
Sommer G, Heise T. Role of the RNA-binding protein La in cancer pathobiology. RNA Biol. 2021;18:218–36.
Chen T, Gu C, Xue C, Yang T, Zhong Y, Liu S, et al. LncRNA-uc002mbe.2 Interacting with hnRNPA2B1 Mediates AKT Deactivation and p21 Up-Regulation Induced by Trichostatin in Liver Cancer Cells. Front Pharm. 2017;8:669.
Wang H, Liang L, Dong Q, Huan L, He J, Li B, et al. Long noncoding RNA miR503HG, a prognostic indicator, inhibits tumor metastasis by regulating the HNRNPA2B1/NF-κB pathway in hepatocellular carcinoma. Theranostics. 2018;8:2814–29.
Meng LD, Shi GD, Ge WL, Huang XM, Chen Q, Yuan H, et al. Linc01232 promotes the metastasis of pancreatic cancer by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the A-Raf-induced MAPK/ERK signaling pathway. Cancer Lett. 2020;494:107–20.
Arcaro A. Targeting the insulin-like growth factor-1 receptor in human cancer. Front Pharm. 2013;4:30.
Riedemann J, Macaulay VM. IGF1R signalling and its inhibition. Endocr-Relat cancer. 2006;13:S33–43.
Werner H, Sarfstein R. Transcriptional and epigenetic control of IGF1R gene expression: implications in metabolism and cancer. Growth Horm IGF Res : Off J Growth Horm Res Soc Int IGF Res Soc. 2014;24:112–8.
Shan YX, Yang TL, Mestril R, Wang PH. Hsp10 and Hsp60 suppress ubiquitination of insulin-like growth factor-1 receptor and augment insulin-like growth factor-1 receptor signaling in cardiac muscle: implications on decreased myocardial protection in diabetic cardiomyopathy. J Biol Chem. 2003;278:45492–8.
Zhang J, Huang FF, Wu DS, Li WJ, Zhan HE, Peng MY, et al. SUMOylation of insulin-like growth factor 1 receptor, promotes proliferation in acute myeloid leukemia. Cancer Lett. 2015;357:297–306.
Zheng Q, Gan H, Yang F, Yao Y, Hao F, Hong L, et al. Cytoplasmic m(1)A reader YTHDF3 inhibits trophoblast invasion by downregulation of m(1)A-methylated IGF1R. Cell Discov. 2020;6:12.
Zhao Z, Qing Y, Dong L, Han L, Wu D, Li Y, et al. QKI shuttles internal m(7)G-modified transcripts into stress granules and modulates mRNA metabolism. Cell. 2023;186:3208–3226.e27.
Pu X, Gu Z, Gu Z. ALKBH5 regulates IGF1R expression to promote the Proliferation and Tumorigenicity of Endometrial Cancer. J Cancer. 2020;11:5612–22.
Clough E, Barrett T. The Gene Expression Omnibus Database. Methods Mol Biol (Clifton, NJ). 2016;1418:93–110.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif). 2001;25:402–8.
Qu L, Ding J, Chen C, Wu ZJ, Liu B, Gao Y, et al. Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA. Cancer Cell. 2016;29:653–68.
Kim D, Paggi JM, Park C, Bennett C, Salzberg SL. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol. 2019;37:907–15.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014;15:1–21.
Han X, Jiang S, Gu Y, Ding L, Zhao E, Cao D, et al. HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1. Cell Death Dis. 2023;14:327.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (82203348, 82103230, 82025029 and 82150114); by grants from the National Key Research and Development Program of China (2022YFC3401001); by grants from the Fundamental Research Funds for the Central Universities; by grants from the Guizhou Science and Technology Department for Basic Research Project (QKHJC-2019-1192 and QKHJC-2020-1Y342); by grants from the Natural Science Basic Research Program of Shanxi Province (202303021222399).
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Author contributions: SG, YW, and XWY. designed research, wrote the paper; YW, XWY, LFL, XQZ, AD, DLS, XFZ, BP, XLC, CZ, FCY, HW, YBZ, TTZ, SZZ and TYC performed research; LQD, SWC analyzed data; LR and SG reviewed the paper.
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Wen, Y., Yang, X., Li, Y. et al. DRAIC mediates hnRNPA2B1 stability and m6A-modified IGF1R instability to inhibit tumor progression. Oncogene 43, 2266–2278 (2024). https://doi.org/10.1038/s41388-024-03071-8
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DOI: https://doi.org/10.1038/s41388-024-03071-8