FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to promote lung adenocarcinoma progression via IKK/NF-κB signaling

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.

Predicting Differences in Treatment Response and Survival Time of Lung Adenocarcinoma Patients Based on a Prognostic Risk Model of Glycolysis-Related Genes

“…FKBP4 encodes a protein that plays a role in immune regulation and basic cellular processes are involved in protein folding and trafficking. Transcriptional activity and nuclear translocation of NF-κB is enhanced to promote LUAD progression through the formation of FKBP4/Hsp90/IKK and FKBP4/Hsp70/RelA complexes ( Zong et al, 2021 ). As a target gene of mir-34A-5p, HMMR can promote tumor growth in LUAD through the HCG18/Mir-34A-5p/HMMR axis ( Li et al, 2020c ).…”

[Retracted] Correlation with Spectral CT Imaging Parameters and Occult Lymph Nodes Metastases in Sufferers with Isolated Lung Adenocarcinoma

“…It is more likely to occur in women and smokers. If the disease is not controlled in time, the condition deteriorates rapidly, and the tumor occupies most of the lungs, which will have a great impact on the patient's breathing and pose a great threat to the patient's life [1][2][3][4]. Isolated lung adenocarcinoma is a special type of lung adenocarcinoma, which only manifests as an isolated pulmonary nodule and is prone to occult lymph nodes metastasis, leading to missed diagnosis and misdiagnosis, delaying the best treatment opportunity, and endangering the patient's life [5,6].…”

Apoptosis-Associated Gene Expression Profiling Is One New Prognosis Risk Predictor of Human Rectal Cancer

“…Similar to prior research, patients with a low CYCS level show weaker apoptosis of cancer cells. As everyone knows, the IKK complex is composed of IKK α , IKK γ , and IKK β (also referred as IKBKB) [ 28 ]. The last one has been verified to be implicated in tumor growth through NF- κ B activation and phosphorylation-dependent suppression of tumor suppressor [ 29 , 30 ].…”