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Background <p>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.</p> Methods <p>Public transcriptomic and clinical datasets, including TCGA, GEO, were integrated to identify c-Myc-associated long noncoding RNAs in PDAC, with <i>LINC01963</i> selected for further investigation. The functional roles of <i>LINC01963</i> were validated using human PDAC cell lines and in vivo proliferation models. The molecular mechanisms underlying c-Myc regulation by <i>LINC01963</i> were explored using RNA pull-down, RIP-seq, RIP-qPCR, Co-IP, mass spectrometry, ubiquitination assays, truncation and site-directed mutagenesis analyses, and dual-luciferase reporter assays. Survival associations were evaluated using Kaplan–Meier analysis and Cox proportional hazards regression.</p> Results <p>Here, the long noncoding RNAs (lncRNAs) highly expressed in PDAC and significantly correlated with <i>c-Myc</i> expression were identified using RNA sequencing datasets. Among them, <i>LINC01963</i> was found to interact with c-Myc, as confirmed by RNA pull-down and RIP-qPCR assays. Furthermore, high <i>LINC01963</i> 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 <i>LINC01963</i> as a key regulator of <i>c-Myc</i> stability, consequently affecting cell cycle through the c-Myc/p21-related signaling pathways. Further investigation revealed that <i>LINC01963</i> enhanced N6-methyladenosine (m⁶A) modification of <i>c-Myc</i> mRNA by protecting methyltransferase-like 3 (METTL3) protein from KDM1B-mediated K48-linked ubiquitination and proteasomal degradation. Intriguingly, <i>LINC01963</i> also stabilized <i>c-Myc</i> mRNA by facilitating the formation of a ternary complex with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and m⁶A-modified <i>c-Myc</i>.</p> Conclusions <p>Our study reveals that <i>LINC01963</i> promotes PDAC tumorigenesis through METTL3/IGF2BP2 axis-coordinated regulation of c-Myc, suggesting a new strategy for indirectly targeting c-Myc.</p>

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LINC01963 promotes pancreatic ductal adenocarcinoma proliferation via METTL3/IGF2BP2 axis-mediated m⁶A modification of c-Myc

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月4日

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  • Qixian Liu,
  • Ruiyu Li,
  • Bohan Liu,
  • Hangqi Liu,
  • Xuqing Shi,
  • Xianglin Yin,
  • Xinping Ju,
  • Sichong Zhang,
  • Jun Wang,
  • Yuhan Zhang,
  • Xiaoding Liu,
  • Dongmei Li,
  • Longyun Chen,
  • Yamei Niu,
  • Huanwen Wu,
  • Zhiyong Liang

摘要

Background

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.

Methods

Public transcriptomic and clinical datasets, including TCGA, GEO, were integrated to identify c-Myc-associated long noncoding RNAs in PDAC, with LINC01963 selected for further investigation. The functional roles of LINC01963 were validated using human PDAC cell lines and in vivo proliferation models. The molecular mechanisms underlying c-Myc regulation by LINC01963 were explored using RNA pull-down, RIP-seq, RIP-qPCR, Co-IP, mass spectrometry, ubiquitination assays, truncation and site-directed mutagenesis analyses, and dual-luciferase reporter assays. Survival associations were evaluated using Kaplan–Meier analysis and Cox proportional hazards regression.

Results

Here, 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 K48-linked ubiquitination and proteasomal 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.

Conclusions

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.