<i>DMDRMR</i> -Mediated Regulation of m6A-Modified <i>CDK4</i> by m6A Reader IGF2BP3 Drives ccRCC Progression

Abstract

Aberrant <i>N</i> ⁶-methyladenosine (m⁶A) modification has emerged as a driver of tumor initiation and progression, yet how long noncoding RNAs (lncRNA) are involved in the regulation of m⁶A 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 m⁶A reader-cooperating lncRNA (<i>DMDRMR</i>) facilitated tumor growth and metastasis in clear cell renal cell carcinoma (ccRCC). Mechanistically, <i>DMDRMR</i> bound insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to stabilize target genes, including the cell-cycle kinase <i>CDK4</i> and three extracellular matrix components (<i>COL6A1, LAMA5</i>, and <i>FN1</i>), by specifically enhancing IGF2BP3 activity on them in an m⁶A-dependent manner. Consequently, <i>DMDRMR</i> and IGF2BP3 enhanced the G₁-S transition, thus promoting cell proliferation in ccRCC. In patients with ccRCC, high coexpression of <i>DMDRMR</i> and IGF2BP3 was associated with poor outcomes. Our findings reveal that <i>DMDRMR</i> cooperates with IGF2BP3 to regulate target genes in an m⁶A-dependent manner and may represent a potential diagnostic, prognostic, and therapeutic target in ccRCC. SIGNIFICANCE: This study demonstrates that the lncRNA <i>DMDRMR</i> acts as a cofactor for IGF2BP3 to stabilize target genes in an m⁶A-dependent manner, thus exerting essential oncogenic roles in ccRCC.