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Full Length Article | Open Access

The stability of FKBP9 maintained by BiP is crucial for glioma progression

Shirong Lia,1Wangxiao Xiab,1Bin Suna,1Weiyan PengcDong YangaJing GaodShuai HeaHua Yangb,eYongjie ZhuaHu ZhoudTingxiu Xiangc( )Qingpeng Kongb( )Xudong Zhaoa( )
Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
The Third People’s Hospital of Yunnan Province, Kunming, Yunnan 650600, China

1 Co-first authors.

Peer review under the responsibility of the Genes & Diseases Editorial Office, in alliance with the Association of Chinese Americans in Cancer Research (ACACR, Baltimore, MD, USA).

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Abstract

FK506-binding protein 9 (FKBP9) is involved in tumor malignancy by resistance to endoplasmic reticulum (ER) stress, and the up-regulation of FKBP9 is associated with patients’ poor prognosis. The current knowledge of the molecular mechanisms is still limited. One previous study showed that FKBP9 could confer glioblastoma cell resistance to ER stress through ASK1-p38 signaling. However, the upstream regulatory mechanism of FKBP9 expression is still indistinct. In this study, we identified the FKBP9 binding proteins using co-immunoprecipitation followed by mass spectrometry. Results showed that FKBP9 interacted with the binding immunoglobulin protein (BiP). BiP bound directly to FKBP9 with high affinity. BiP prolonged the half-life of the FKBP9 protein and stabilized the FKBP9 protein. BiP and FKBP9 protein levels were positively correlated in patients with glioma, and patients with high expression of BiP and FKBP9 showed a worse prognosis. Further studies showed that FKBP9 knockout in genetically engineered mice inhibited intracranial glioblastoma formation and prolonged survival by decreasing cellular proliferation and ER stress-induced CHOP-related apoptosis. Moreover, normal cells may depend less on FKBP9, as shown by the absence of apoptosis upon FKBP9 knockdown in a non-transformed human cell line and overall normal development in homozygous knockout mice. These findings suggest an important role of BiP-regulated FKBP9-associated signaling in glioma progression and the BiP–FKBP9 axis may be a potential therapeutic target for glioma.

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Genes & Diseases
Article number: 101123
Cite this article:
Li S, Xia W, Sun B, et al. The stability of FKBP9 maintained by BiP is crucial for glioma progression. Genes & Diseases, 2024, 11(6): 101123. https://doi.org/10.1016/j.gendis.2023.101123

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Received: 17 April 2023
Revised: 12 July 2023
Accepted: 04 August 2023
Published: 22 September 2023
© 2023 The Authors.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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