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Background <p>Ovarian cancer (OC) is a lethal gynecologic malignancy with limited therapeutic success due to late diagnosis and therapy resistance. Endoplasmic reticulum (ER) stress and ER-associated degradation (ERAD) are key to tumor adaptation, yet the mechanisms sustaining ER homeostasis in OC remain poorly defined.</p> Methods <p>We combined multi-omics analyses, tissue microarrays, and in vitro and in vivo models. Functional assays involved COPB2 knockdown or overexpression in OC cells, xenografts in nude mice, and mechanistic studies including protein interaction and glycoproteomic analyses.</p> Results <p>COPB2 was significantly upregulated in OC and associated with poor prognosis. It promoted cell proliferation and survival by alleviating ER stress and suppressing apoptosis. Mechanistically, COPB2 interacted with EDEM3, a key ERAD enzyme, enhancing its ER localization and mannose-trimming function. COPB2 depletion impaired EDEM3 activity, resulting in glycan processing defects and ER stress accumulation. In vivo, COPB2 overexpression accelerated tumor growth.</p> Conclusions <p>This study identifies a novel COPB2–EDEM3 axis that maintains ER homeostasis and drives OC progression. Targeting this axis may offer new opportunities for therapeutic intervention and biomarker development.</p>

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COPB2 facilitates EDEM3-mediated mannose trimming to sustain ER homeostasis in ovarian cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月30日

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  • Dong-Xue Li,
  • Ni Yang,
  • Lan-Yu Hua,
  • Jun-Jie Wang,
  • Dilinazi Abudujilile,
  • Zhi-Gang Zhang,
  • Peng-Feng Zhu,
  • Ting-Yan Shi,
  • Rong Zhang

摘要

Background

Ovarian cancer (OC) is a lethal gynecologic malignancy with limited therapeutic success due to late diagnosis and therapy resistance. Endoplasmic reticulum (ER) stress and ER-associated degradation (ERAD) are key to tumor adaptation, yet the mechanisms sustaining ER homeostasis in OC remain poorly defined.

Methods

We combined multi-omics analyses, tissue microarrays, and in vitro and in vivo models. Functional assays involved COPB2 knockdown or overexpression in OC cells, xenografts in nude mice, and mechanistic studies including protein interaction and glycoproteomic analyses.

Results

COPB2 was significantly upregulated in OC and associated with poor prognosis. It promoted cell proliferation and survival by alleviating ER stress and suppressing apoptosis. Mechanistically, COPB2 interacted with EDEM3, a key ERAD enzyme, enhancing its ER localization and mannose-trimming function. COPB2 depletion impaired EDEM3 activity, resulting in glycan processing defects and ER stress accumulation. In vivo, COPB2 overexpression accelerated tumor growth.

Conclusions

This study identifies a novel COPB2–EDEM3 axis that maintains ER homeostasis and drives OC progression. Targeting this axis may offer new opportunities for therapeutic intervention and biomarker development.