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DRAIC mediates hnRNPA2B1 stability and m6A-modified IGF1R instability to inhibit tumor progression

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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Fig. 1: DRAIC represses tumor cell proliferation and metastasis.
Fig. 2: DRAIC directly binds with hnRNPA2B1.
Fig. 3: DRAIC blocks hnRNPA2B1 ubiquitination and degradation.
Fig. 4: IGF1R is negatively regulated by DRAIC and hnRNPA2B1.
Fig. 5: DRAIC and hnRNPA2B1 function through IGF1R in ccRCC.
Fig. 6: DRAIC and hnRNPA2B1 promote IGF1R mRNA degradation in an m6A-dependent manner.
Fig. 7: The identification of IGF1R m6A sites.

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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.

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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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Correspondence to Li Ren or Shan Gao.

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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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