FKBP9 promotes the malignant behavior of glioblastoma cells and confers resistance to endoplasmic reticulum stress inducers

Abstract

Background: FK506-binding protein 9 (FKBP9) is amplified in high-grade gliomas (HGGs). However, the roles and mechanism(s) of FKBP9 in glioma are unknown. Methods: The expression of FKBP9 in clinical glioma tissues was detected by immunohistochemistry (IHC). The correlation between FKBP9 expression levels and the clinical prognosis of glioma patients was examined by bioinformatic analysis. Glioblastoma (GBM) cell lines stably depleted of FKBP9 were established using lentiviruses expressing shRNAs against FKBP9. The effects of FKBP9 on GBM cells were determined by cell-based analyses, including anchorage-independent growth, spheroid formation, transwell invasion assay, confocal microscopy, immunoblot (IB) and coimmunoprecipitation assays. In vivo tumor growth was determined in both chick chorioallantoic membrane (CAM) and mouse xenograft models. Results: High FKBP9 expression correlated with poor prognosis in glioma patients. Knockdown of FKBP9 markedly suppressed the malignant phenotype of GBM cells in vitro and inhibited tumor growth in vivo. Mechanistically, FKBP9 expression induced the activation of p38MAPK signaling via ASK1. Furthermore, ASK1-p38 signaling contributed to the FKBP9-mediated effects on GBM cell clonogenic growth. In addition, depletion of FKBP9 activated the IRE1α-XBP1 pathway, which played a role in the FKBP9-mediated oncogenic effects. Importantly, FKBP9 expression conferred GBM cell resistance to endoplasmic reticulum (ER) stress inducers that caused FKBP9 ubiquitination and degradation.Conclusions: Our findings suggest an oncogenic role for FKBP9 in GBM and reveal FKBP9 as a novel mediator in the IRE1α-XBP1 pathway.

Identification of Pan-Cancer Biomarkers Based on the Gene Expression Profiles of Cancer Cell Lines

“…A recent study has found that FKBP9 could be an independent prognostic marker for predicting the poor prognosis of patients with prostate cancer; that high FKBP9 levels and short biochemical-recurrence-free survival are significantly correlated ( p = 0.041); and that FKBP9 may be a cancer promoter that enhances prostate cancer progression ( Jiang et al, 2020 ). Another study found that FKBP9 is a critical factor for promoting the malignant behaviors of glioblastoma cells; high FKBP9 level is related to poor prognosis and could confer malignant cells with the capability to resist endoplasmic reticulum stress inducers ( Xu et al, 2020 ). Other studies have also confirmed that FKBP9 is connected with other cancers, such as colorectal and breast cancers ( Bianchini et al, 2006 ; Chang et al, 2020 ).…”

A Preclinical Investigation of GBM-N019 as a Potential Inhibitor of Glioblastoma via Exosomal mTOR/CDK6/STAT3 Signaling

“…Additionally, STAT3 and CDK6 have been associated with cancer-associated fibroblast and immune cell infiltration and are considered biomarkers of poor prognosis in multiple cancers [ 23 ]. Furthermore, our analysis of PPI clustering networks of mTOR, STAT3, and CDK6 identified some functional partners that are known regulators of GBM growth and invasive properties [ 71 , 72 , 73 , 74 ]. These PPI clustering networks were also found to be enriched in pathways and ontologies that are associated with tumor progression and drug resistance.…”

Oncolytic Virus-Induced Autophagy in Glioblastoma

“…The unfolded protein response is a process activated due to overwhelming ER stress and the inability of tumor cells to counteract it. It remains unknown at which point the UPR leads to cell death, how it promotes cellular apoptosis, and/or when it promotes cell survival [ 41 ]. UPR has long been viewed as an adaptive program to sustain cellular homeostasis to counterbalance ER stress.…”