Abstract
FKBP4 belongs to the family of immunophilins, which serve as a regulator for steroid receptor activity. Thus, FKBP4 has been recognized to play a critical role in several hormone-dependent cancers, including breast and prostate cancer. However, there is still no research to address the role of FKBP4 on lung adenocarcinoma (LUAD) progression. We found that FKBP4 expression was elevated in LUAD samples and predicted significantly shorter overall survival based on TCGA and our cohort of LUAD patients. Furthermore, FKBP4 robustly increased the proliferation, metastasis, and invasion of LUAD in vitro and vivo. Mechanistic studies revealed the interaction between FKBP4 and IKK kinase complex. We found that FKBP4 potentiated IKK kinase activity by interacting with Hsp90 and IKK subunits and promoting Hsp90/IKK association. Also, FKBP4 promotes the binding of IKKγ to IKKβ, which supported the facilitation role in IKK complex assembly. We further identified that FKBP4 TPR domains are essential for FKBP4/IKK interaction since its association with Hsp90 is required. In addition, FKBP4 PPIase domains are involved in FKBP4/IKKγ interaction. Interestingly, the association between FKBP4 and Hsp70/RelA favors the transport of RelA toward the nucleus. Collectively, FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to potentiate the transcriptional activity and nuclear translocation of NF-κB, thereby promoting LUAD progression. Our findings suggest that FKBP4 may function as a prognostic biomarker of LUAD and provide a newly mechanistic insight into modulating IKK/NF-κB signaling.
Highlights
Lung cancer is the most common cause of cancerrelated mortality worldwide[1,2]
FKBP4 is highly expressed in lung adenocarcinoma (LUAD) and correlated with poor prognosis To explore the potential role of FKBP4 in LUAD progression, we analyzed the RNA-seq data (FPKM values) from The Cancer Genome Atlas (TCGA) database
We found that the FKBP4 expression levels were notably associated with gender, tumor size, and clinical TNM stage according to TCGA database (Table 1)
Summary
Lung cancer is the most common cause of cancerrelated mortality worldwide[1,2]. Approximately 85% of diagnosed cases are classified as non-small-cell lung cancer (NSCLC), with lung adenocarcinoma (LUAD) being the predominant histological subtype[3]. Official journal of the Cell Death Differentiation Association. (IL-1)), pathogen-associated molecules (e.g., lipopolysaccharide (LPS)), and chemical inducers (e.g., phorbol12-myristate-13-acetate (PMA)) that activate the tripartite IκB kinase complex (IKK; IKKα/IKKβ/IKKγ). FK506-binding proteins (FKBPs) belong to the family of immunophilins, which are structurally characterized by the existence of peptidyl-prolyl isomerase (PPIase) domains[9]. In addition to their well-established role in immunosuppression, FKBPs are involved in numerous cellular processes, such as protein trafficking, transcriptional regulation, protein folding, and signal transduction[10]. The FK1 domain confers PPIase enzymatic activity that can be inhibited by the immunosuppressants FK506 and rapamycin, while the FK2 domain seems to play a structural role. High-molecularweight immunophilins, such as FKBP4 and FKBP5, possess C-terminal tetratricopeptide repeat (TPR) domains, which are able to form complexes with the molecular chaperone Hsp9011, and participate in protein−protein interactions[12]
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