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<p>NSUN2-dependent RNA m<sup>5</sup>C methylation is essential for RNA stability, cellular metabolism, and intracellular transport. Aberrant <i>YAP</i> expression is closely associated with tumorigenesis and progression in human cancers. However, the molecular mechanism by which m⁵C regulates the growth and metastasis of NSCLC through modulating <i>YAP</i> expression remains incompletely understood. Our results demonstrate that YAP and NSUN2 play analogous roles in regulating NSCLC cell growth, migration, invasion, and EMT. NSUN2 increased m<sup>5</sup>C modification of <i>YAP</i> mRNA. ALYREF and YBX1 combined and then interacted with <i>YAP</i> mRNA in an m<sup>5</sup>C-dependent manner to increase <i>YAP</i> stability and translation. Importantly, NSUN2, ALYREF and YBX1 bind to each other and affected their interaction with <i>YAP</i> mRNA. Mechanistically, NSUN2 first initiates the m<sup>5</sup>C within <i>YAP</i> mRNA and then ALYREF recognizes m<sup>5</sup>C modification on <i>YAP</i> mRNA, YBX1 was more likely to bind to the transitive m<sup>5</sup>C from ALYREF and then promoted <i>YAP</i> mRNA stability through impeding the combination between AGO2 and <i>YAP</i> mRNA whereby increasing the expression of <i>YAP</i> with interaction with eIF3a and thus excessive cell growth and metastasis via regulation of YAP’s target genes of CTGF, Cyr61 MMP2, MMP9 in NSCLC. Moreover, NSUN2 is transcriptionally activated by the YAP-TEAD2 complex, forming a positive feedback loop that promotes tumor growth and metastasis, a process effectively suppressed by m<sup>5</sup>C inhibitors both in vivo and in vitro. Furthermore, our presented findings suggest that NSUN2 promotes tumor growth and metastasis by increasing ALYREF/YBX1-mediated <i>YAP</i> expression in NSCLC and effective inhibition of m<sup>5</sup>C modification might provide a potential treatment strategy for NSCLC.</p>

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NSUN2 promoted tumor growth and metastatic via m5C-regulation of YAP through ALYREF/YBX1 axis in NSCLC

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月7日

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  • Rui Li,
  • Dan Jin,
  • Shuang Shao,
  • Jiwei Guo

摘要

NSUN2-dependent RNA m5C methylation is essential for RNA stability, cellular metabolism, and intracellular transport. Aberrant YAP expression is closely associated with tumorigenesis and progression in human cancers. However, the molecular mechanism by which m⁵C regulates the growth and metastasis of NSCLC through modulating YAP expression remains incompletely understood. Our results demonstrate that YAP and NSUN2 play analogous roles in regulating NSCLC cell growth, migration, invasion, and EMT. NSUN2 increased m5C modification of YAP mRNA. ALYREF and YBX1 combined and then interacted with YAP mRNA in an m5C-dependent manner to increase YAP stability and translation. Importantly, NSUN2, ALYREF and YBX1 bind to each other and affected their interaction with YAP mRNA. Mechanistically, NSUN2 first initiates the m5C within YAP mRNA and then ALYREF recognizes m5C modification on YAP mRNA, YBX1 was more likely to bind to the transitive m5C from ALYREF and then promoted YAP mRNA stability through impeding the combination between AGO2 and YAP mRNA whereby increasing the expression of YAP with interaction with eIF3a and thus excessive cell growth and metastasis via regulation of YAP’s target genes of CTGF, Cyr61 MMP2, MMP9 in NSCLC. Moreover, NSUN2 is transcriptionally activated by the YAP-TEAD2 complex, forming a positive feedback loop that promotes tumor growth and metastasis, a process effectively suppressed by m5C inhibitors both in vivo and in vitro. Furthermore, our presented findings suggest that NSUN2 promotes tumor growth and metastasis by increasing ALYREF/YBX1-mediated YAP expression in NSCLC and effective inhibition of m5C modification might provide a potential treatment strategy for NSCLC.