Scholarlink

<p>Metastasis remains the primary cause of mortality in lung adenocarcinoma (LUAD) patients. However, the molecular mechanisms underlying LUAD cell metastasis are only partially elucidated. Here, by performing integrated bioinformatic analysis of clinical data, RNA-binding protein (RBP) NOVA2 is identified as a pivotal LUAD metastasis-associated regulator. NOVA2 expression is elevated in metastatic LUAD tissues and correlates with poor prognosis of LUAD patients. Functionally, NOVA2 depletion suppresses epithelial-mesenchymal transition (EMT), migration, and invasion in vitro, and attenuates LUAD cell metastasis in vivo. Mechanistically, histone acetyltransferase p300 augments H3K27 acetylation level and facilitates the binding of STAT3 to the <i>NOVA2</i> promoter, which in turn promotes <i>NOVA2</i> transcription. Increased NOVA2 expression induces exon skipping (exons 6–7) in <i>SMAD4</i> to generate a truncated splicing isoform (termed Δ-SMAD4). The resulting Δ-SMAD4 isoform evades E3 ubiquitin ligase β-TrCP-mediated ubiquitination, maintaining its ability to form complex with SMAD3 (R-SMAD) and sustain TGF-β/SMAD signaling. Moreover, in NOVA2-overexpressing LUAD cells, Δ-SMAD4 knockdown has stronger inhibitory effects on TGF-β-induced EMT and invasion than does SMAD4 knockdown. In summary, our findings identify a novel mechanism by which STAT3-mediated transcriptional upregulation of NOVA2 promotes SMAD4 splicing in metastatic LUAD, and suggest that the STAT3-NOVA2-Δ-SMAD4 axis drives EMT and LUAD metastasis, which may be a promising therapeutic target for treating LUAD.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

STAT3-mediated transactivation of NOVA2 promotes lung adenocarcinoma metastasis by splicing SMAD4

  • 期刊论文

  • 发表日期：

    2026年4月1日

查看全文
  • Shengjie Wang,
  • Xin Tong,
  • Runfeng Sun,
  • Xinyi Xia,
  • Donglai Chen,
  • Zhao Wang,
  • Hao Shi,
  • Chenzhuo Wu,
  • Xiaoxiao Guo,
  • Die Hu,
  • Ersuo Jin,
  • Hong-Tao Zhang

摘要

Metastasis remains the primary cause of mortality in lung adenocarcinoma (LUAD) patients. However, the molecular mechanisms underlying LUAD cell metastasis are only partially elucidated. Here, by performing integrated bioinformatic analysis of clinical data, RNA-binding protein (RBP) NOVA2 is identified as a pivotal LUAD metastasis-associated regulator. NOVA2 expression is elevated in metastatic LUAD tissues and correlates with poor prognosis of LUAD patients. Functionally, NOVA2 depletion suppresses epithelial-mesenchymal transition (EMT), migration, and invasion in vitro, and attenuates LUAD cell metastasis in vivo. Mechanistically, histone acetyltransferase p300 augments H3K27 acetylation level and facilitates the binding of STAT3 to the NOVA2 promoter, which in turn promotes NOVA2 transcription. Increased NOVA2 expression induces exon skipping (exons 6–7) in SMAD4 to generate a truncated splicing isoform (termed Δ-SMAD4). The resulting Δ-SMAD4 isoform evades E3 ubiquitin ligase β-TrCP-mediated ubiquitination, maintaining its ability to form complex with SMAD3 (R-SMAD) and sustain TGF-β/SMAD signaling. Moreover, in NOVA2-overexpressing LUAD cells, Δ-SMAD4 knockdown has stronger inhibitory effects on TGF-β-induced EMT and invasion than does SMAD4 knockdown. In summary, our findings identify a novel mechanism by which STAT3-mediated transcriptional upregulation of NOVA2 promotes SMAD4 splicing in metastatic LUAD, and suggest that the STAT3-NOVA2-Δ-SMAD4 axis drives EMT and LUAD metastasis, which may be a promising therapeutic target for treating LUAD.