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 pre-vious 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 immu-noglobulin 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 forglioma.
