LINC01963 Promotes Pancreatic Cancer Proliferation via METTL3/IGF2BP2 Axis-Mediated m6A Modification of c-Myc
C-Myc overexpression is an important molecular hallmark of pancreatic ductal adenocarcinoma (PDAC), but directly targeting c-Myc is extremely challenging. Identifying key upstream factors involved in c-Myc overexpression provides promising indirect targets for c-Myc. Herein, the long noncoding RNAs (lncRNAs) highly expressed in PDAC and significantly correlated with c-Myc expression were identified using RNA sequencing datasets. Among them, LINC01963 was found to interact with c-Myc, as confirmed by RNA pull-down and RIP-qPCR assays. Furthermore, high LINC01963 expression was correlated with poor PDAC prognosis, and functional studies demonstrated that its knockdown inhibited PDAC cell proliferation and xenograft tumor growth. Mechanistic studies identified LINC01963 as a key regulator of c-Myc stability, consequently affecting cell cycle through the c-Myc/p21-related signaling pathways. Further investigation revealed that LINC01963 enhanced N6-methyladenosine (m6A) modification of c-Myc mRNA by protecting methyltransferase-like 3 (METTL3) protein from KDM1B-mediated ubiquitin-proteasome degradation. Intriguingly, LINC01963 also stabilized c-Myc mRNA by facilitating the formation of a ternary complex with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and m6A-modified c-Myc. Our study reveals that LINC01963 promotes PDAC tumorigenesis through METTL3/IGF2BP2 axis-coordinated regulation of c-Myc, suggesting a new strategy for indirectly targeting c-Myc. Overall design: LINC01963 Promotes Pancreatic Cancer Proliferation via METTL3/IGF2BP2 Axis-Mediated m6A Modification of c-Myc