BRAP maintains SEC24D stability to regulate ER stress and promote cervical adenocarcinoma progression
7 affiliations
- 1Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital, Zhuhai Institute of Translational Medicine, Zhuhai Medical College of Jinan University
- 2Department of Pathology, the Second Xiangya Hospital, Central South University
- 3Department of Physiology, Xiangya School of Basic Medical Science, Central South University
- 4Department of Gynecology, Zhuhai People’s Hospital, The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University
- 5Section of Gastroenterology, and Department of Pathology and Laboratory Medicine, Boston University School of Medicine
- 6Maternal & Child Health Research Institute, Zhuhai Center for Maternal and Child Health Care, Medical Education Center of Jinan University
- 7Department of Gynecology, Zhuhai Center for Maternal and Child Health Care, Medical Education Center of Jinan University
Abstract
Background Cervical adenocarcinoma (ADC) exhibits a poorer prognosis than cervical squamous cell carcinoma and lacks effective targeted therapies. Bombesin receptor- activated protein (BRAP, encoded by C6orf89) has been implicated in cell proliferation and stress responses in multiple biological contexts; however, its role in ADC progression and endoplasmic reticulum (ER) homeostasis remains unknown. Methods BRAP expression was evaluated in human cervical adenocarcinoma (ADC) tissues by immunohistochemistry and western blotting, and its clinicopathological significance was analyzed. BRAP function was investigated by siRNA-mediated knockdown in HeLa and SiHa cells using proliferation, apoptosis, migration, invasion, and epithelial–mesenchymal transition (EMT) assays, and further validated in xenograft models. Ultrastructural alterations were examined by transmission electron microscopy. BRAP-interacting proteins were identified by yeast two-hybrid screening and validated by co-immunoprecipitation. ER stress, ER exit site (ERES) homeostasis, and autophagic flux were evaluated, and rescue experiments were performed by re-expression of BRAP or SEC24D. Results BRAP was markedly upregulated in cervical adenocarcinoma tissues and was associated with poor tumor differentiation. BRAP depletion selectively inhibited proliferation, migration, invasion, and EMT while promoting apoptosis in ADC-derived HeLa cells, but not in squamous cell carcinoma-derived SiHa cells. Mechanistically, BRAP deficiency disrupted ER homeostasis and selectively activated the PERK–ATF4–DDIT3/CHOP branch of the unfolded protein response (UPR), whereas pharmacological inhibition with GSK2606414 largely reversed these phenotypic alterations. We identified the COPII cargo adaptor SEC24D as a novel BRAP-interacting protein. BRAP maintained SEC24D protein stability by preventing excessive autophagy–lysosome-mediated degradation, thereby preserving ERES number and function, as reflected by SEC16A-positive ERES and peripheral LMAN1-positive structures, and maintaining ER–Golgi trafficking homeostasis. Restoration of SEC24D rescued ERES defects, attenuated PERK-dependent UPR activation, and reversed the impaired proliferation, migration, invasion, apoptosis, and EMT induced by BRAP depletion. Conclusion BRAP promotes cervical adenocarcinoma progression by maintaining SEC24D stability and preserving ERES organization and function, thereby sustaining COPII-dependent ER export and ER homeostasis. Disruption of the BRAP–SEC24D axis impairs ERES integrity, activates PERK-dependent ER stress, and suppresses malignant phenotypes. These findings identify BRAP as a previously unrecognized regulator of ER homeostasis and establish the BRAP–SEC24D signaling axis as a potential therapeutic target for cervical adenocarcinoma.
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BibTeX
@article{wang2026brap,
title = {{BRAP maintains SEC24D stability to regulate ER stress and promote cervical adenocarcinoma progression}},
author = {Hui Wang and Yingying Li and Jiaoyun Zheng and Jie Wang and Junyi Duan and Yuhuan Wang and Horst Christian Weber and Quanli Yang and Xiangping Qu and Mubiao Liu},
journal = {Journal of Translational Medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08780-0},
url = {https://doi.org/10.1186/s12967-026-08780-0},
note = {CC BY},
}
RIS
TY - JOUR
TI - BRAP maintains SEC24D stability to regulate ER stress and promote cervical adenocarcinoma progression
AU - Hui Wang
AU - Yingying Li
AU - Jiaoyun Zheng
AU - Jie Wang
AU - Junyi Duan
AU - Yuhuan Wang
AU - Horst Christian Weber
AU - Quanli Yang
AU - Xiangping Qu
AU - Mubiao Liu
PY - 2026
DA - 2026/08/01
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-08780-0
UR - https://doi.org/10.1186/s12967-026-08780-0
AB - Background Cervical adenocarcinoma (ADC) exhibits a poorer prognosis than cervical squamous cell carcinoma and lacks effective targeted therapies. Bombesin receptor- activated protein (BRAP, encoded by C6orf89) has been implicated in cell proliferation and stress responses in multiple biological contexts; however, its role in ADC progression and endoplasmic reticulum (ER) homeostasis remains unknown. Methods BRAP expression was evaluated in human cervical adenocarcinoma (ADC) tissues by immunohistochemistry and western blotting, and its clinicopathological significance was analyzed. BRAP function was investigated by siRNA-mediated knockdown in HeLa and SiHa cells using proliferation, apoptosis, migration, invasion, and epithelial–mesenchymal transition (EMT) assays, and further validated in xenograft models. Ultrastructural alterations were examined by transmission electron microscopy. BRAP-interacting proteins were identified by yeast two-hybrid screening and validated by co-immunoprecipitation. ER stress, ER exit site (ERES) homeostasis, and autophagic flux were evaluated, and rescue experiments were performed by re-expression of BRAP or SEC24D. Results BRAP was markedly upregulated in cervical adenocarcinoma tissues and was associated with poor tumor differentiation. BRAP depletion selectively inhibited proliferation, migration, invasion, and EMT while promoting apoptosis in ADC-derived HeLa cells, but not in squamous cell carcinoma-derived SiHa cells. Mechanistically, BRAP deficiency disrupted ER homeostasis and selectively activated the PERK–ATF4–DDIT3/CHOP branch of the unfolded protein response (UPR), whereas pharmacological inhibition with GSK2606414 largely reversed these phenotypic alterations. We identified the COPII cargo adaptor SEC24D as a novel BRAP-interacting protein. BRAP maintained SEC24D protein stability by preventing excessive autophagy–lysosome-mediated degradation, thereby preserving ERES number and function, as reflected by SEC16A-positive ERES and peripheral LMAN1-positive structures, and maintaining ER–Golgi trafficking homeostasis. Restoration of SEC24D rescued ERES defects, attenuated PERK-dependent UPR activation, and reversed the impaired proliferation, migration, invasion, apoptosis, and EMT induced by BRAP depletion. Conclusion BRAP promotes cervical adenocarcinoma progression by maintaining SEC24D stability and preserving ERES organization and function, thereby sustaining COPII-dependent ER export and ER homeostasis. Disruption of the BRAP–SEC24D axis impairs ERES integrity, activates PERK-dependent ER stress, and suppresses malignant phenotypes. These findings identify BRAP as a previously unrecognized regulator of ER homeostasis and establish the BRAP–SEC24D signaling axis as a potential therapeutic target for cervical adenocarcinoma.
SN - 1479-5876
ER -