-Mediated Regulation of mA-Modified by mA Reader IGF2BP3 Drives ccRCC Progression.

Aberrant -methyladenosine (mA) modification has emerged as a driver of tumor initiation and progression, yet how long noncoding RNAs (lncRNA) are involved in the regulation of mA remains unknown. Here we utilize data from 12 cancer types from The Cancer Genome Atlas to comprehensively map lncRNAs that are potentially deregulated by DNA methylation. A novel DNA methylation-deregulated and RNA mA reader-cooperating lncRNA () facilitated tumor growth and metastasis in clear cell renal cell carcinoma (ccRCC). Mechanistically, bound insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to stabilize target genes, including the cell-cycle kinase and three extracellular matrix components (, and ), by specifically enhancing IGF2BP3 activity on them in an mA-dependent manner. Consequently, and IGF2BP3 enhanced the G-S transition, thus promoting cell proliferation in ccRCC. In patients with ccRCC, high coexpression of and IGF2BP3 was associated with poor outcomes. Our findings reveal that cooperates with IGF2BP3 to regulate target genes in an mA-dependent manner and may represent a potential diagnostic, prognostic, and therapeutic target in ccRCC. SIGNIFICANCE: This study demonstrates that the lncRNA acts as a cofactor for IGF2BP3 to stabilize target genes in an mA-dependent manner, thus exerting essential oncogenic roles in ccRCC.