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

Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in cancer, however, posttranscriptional regulation such as N 6 -methyladenosine (m 6 A) 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 m 6 A modified- IGF1R , leading to inhibition of ccRCC progression. Moreover, four m 6 A 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 m 6 A-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 m 6 A-modified RNA and ubiquitin-modified protein.