Scholarlink

<p>Glioblastoma (GBM) is characterized by the highly infiltrative growth of cancer cells into the surrounding brain parenchyma. DnaJ Heat Shock Protein Family (Hsp40) Member C10 (DNAJC10, also known as ERDJ5&#xa0;and PDIA19), involved in endoplasmic reticulum-associated degradation (ERAD), has been identified as a tumor suppressor in several cancers. However, its precise role and underlying mechanism in GBM remain unclear. We found that DNAJC10 expression is downregulated in GBM patients and correlated with poor survival outcomes. Overexpression of <i>DNAJC10</i> reduced GBM cell migration and invasion in vitro, while its knockdown promotes these processes. Moreover, <i>DNAJC10</i> overexpression inhibits infiltrative growth of GBM cells, suppresses tumor propagation and prolongs survival in xenografted mice. Mechanistically, DNAJC10 regulates multiple molecules and pathways involved in cell motility, including the epidermal growth factor receptor (EGFR) pathway. Importantly, DNAJC10 overexpression decreases <i>EGFR</i> transcription by inhibiting spliced X-box binding protein 1 (XBP-1s). DNAJC10 regulates XBP-1s splicing through the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response (UPR). XBP-1s binds the EGFR promoter and enhances recruitment of SET7/9 methyltransferase, H3K4me3, and H3K4me1. Pharmacological inhibition of histone methylation attenuates XBP-1s-induced <i>EGFR</i> transcription, indicating XBP-1s promotes <i>EGFR</i> expression via recruiting SET7/9 for H3K4 methylation. XBP-1s overexpression reverses DNAJC10-mediated <i>EGFR</i> downregulation. Collectively, DNAJC10 suppresses <i>EGFR</i> transcription by inhibiting the UPR IRE1α-XBP-1s axis, reducing SET7/9 recruitment and H3K4 methylation at the <i>EGFR</i> promoter. Targeting DNAJC10 or XBP-1s could be a potential approach for inhibiting GBM infiltration and may represent a novel avenue for GBM treatment.</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

Endoplasmic reticulum-resident protein DNAJC10 inhibits glioblastoma metastasis by suppressing XBP-1s-driven EGFR transcription

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月24日

查看全文
  • Erdi Zhao,
  • Yue Yu,
  • Yingli Gao,
  • Teng Li,
  • Shiyu Hao,
  • Meiyang Chen,
  • Ming Xu,
  • Sinkemani Arjun,
  • Chunyan Yang,
  • Yancun Yin,
  • Minjing Li

摘要

Glioblastoma (GBM) is characterized by the highly infiltrative growth of cancer cells into the surrounding brain parenchyma. DnaJ Heat Shock Protein Family (Hsp40) Member C10 (DNAJC10, also known as ERDJ5 and PDIA19), involved in endoplasmic reticulum-associated degradation (ERAD), has been identified as a tumor suppressor in several cancers. However, its precise role and underlying mechanism in GBM remain unclear. We found that DNAJC10 expression is downregulated in GBM patients and correlated with poor survival outcomes. Overexpression of DNAJC10 reduced GBM cell migration and invasion in vitro, while its knockdown promotes these processes. Moreover, DNAJC10 overexpression inhibits infiltrative growth of GBM cells, suppresses tumor propagation and prolongs survival in xenografted mice. Mechanistically, DNAJC10 regulates multiple molecules and pathways involved in cell motility, including the epidermal growth factor receptor (EGFR) pathway. Importantly, DNAJC10 overexpression decreases EGFR transcription by inhibiting spliced X-box binding protein 1 (XBP-1s). DNAJC10 regulates XBP-1s splicing through the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response (UPR). XBP-1s binds the EGFR promoter and enhances recruitment of SET7/9 methyltransferase, H3K4me3, and H3K4me1. Pharmacological inhibition of histone methylation attenuates XBP-1s-induced EGFR transcription, indicating XBP-1s promotes EGFR expression via recruiting SET7/9 for H3K4 methylation. XBP-1s overexpression reverses DNAJC10-mediated EGFR downregulation. Collectively, DNAJC10 suppresses EGFR transcription by inhibiting the UPR IRE1α-XBP-1s axis, reducing SET7/9 recruitment and H3K4 methylation at the EGFR promoter. Targeting DNAJC10 or XBP-1s could be a potential approach for inhibiting GBM infiltration and may represent a novel avenue for GBM treatment.