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<p>ZMIZ2, a transcription co-activator, is frequently overexpressed in various tumors. However, its functional role and molecular mechanisms in driving non-small cell lung cancer (NSCLC) metastasis remain elusive. Our study reveals that ZMIZ2 is significantly overexpressed in lung adenocarcinoma (LUAD) tissues and is strongly correlated with adverse patient outcomes. Elevated ZMIZ2 expression enhances LUAD cell proliferation, migration, invasion and metastasis, whereas ZMIZ2 depletion exerts opposing effects. Mechanistically, ZMIZ2 physically interacts with PIN1 to trigger K63-linked ubiquitination-dependent PIN1 stabilization, which consequently hyperactivates the PI3K/AKT signaling axis. Notably, silencing PIN1 expression significantly attenuated ZMIZ2-mediated activation of the PI3K/AKT signaling pathway and inhibited LUAD cell proliferation, migration and invasion. Collectively, our findings establish ZMIZ2 as a novel metastasis driver that orchestrates LUAD progression through PIN1-mediated PI3K/AKT pathway activation, providing a rationale for targeting this axis in precision oncology.</p>

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ZMIZ2 interacts with PIN1 to promote lung adenocarcinoma EMT and metastasis via activation of the PI3K/AKT pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月28日

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  • Zhiyue Su,
  • Yuhong Wang,
  • Ersuo Jin,
  • Feifei Wang,
  • Weiwei Zhang,
  • Yingxi Zhang,
  • Zeyi Liu,
  • Shengjie Wang,
  • Hongli Yang,
  • Chang Qi,
  • DongMei Gu,
  • Xia Liu,
  • Lingchuan Guo,
  • Hong-Tao Zhang,
  • Zhe Lei

摘要

ZMIZ2, a transcription co-activator, is frequently overexpressed in various tumors. However, its functional role and molecular mechanisms in driving non-small cell lung cancer (NSCLC) metastasis remain elusive. Our study reveals that ZMIZ2 is significantly overexpressed in lung adenocarcinoma (LUAD) tissues and is strongly correlated with adverse patient outcomes. Elevated ZMIZ2 expression enhances LUAD cell proliferation, migration, invasion and metastasis, whereas ZMIZ2 depletion exerts opposing effects. Mechanistically, ZMIZ2 physically interacts with PIN1 to trigger K63-linked ubiquitination-dependent PIN1 stabilization, which consequently hyperactivates the PI3K/AKT signaling axis. Notably, silencing PIN1 expression significantly attenuated ZMIZ2-mediated activation of the PI3K/AKT signaling pathway and inhibited LUAD cell proliferation, migration and invasion. Collectively, our findings establish ZMIZ2 as a novel metastasis driver that orchestrates LUAD progression through PIN1-mediated PI3K/AKT pathway activation, providing a rationale for targeting this axis in precision oncology.