Pan-cancer analysis of the prognostic and immunological role of FKBP4.

Objectives: Our previous studies revealed the significant roles of FK506-binding protein 4 (FKBP4) in tumorigenesis, however, there has been no pan-cancer analysis of FKBP4. Using bioinformatics, the current study reported the expression and prognostic role of FKBP4, and the correlation between FKBP4 and clinicopathological parameters, methylation, molecular network, immunological traits and drug sensitivity. Methods: RNA sequencing data, somatic mutation, and related clinical information were obtained from TCGA using UCSC Xena. The association between FKBP4 expression and clinical features was assessed using TISIDB. The relationships between FKBP4 expression and tumour stage, OS, DSS, DFS, and PFS were analysed using univariate cox regression analysis. The radar plots for TMB and MSI were obtained using "Fmsb" R package. UALCAN was used to explore the effect of FKBP4 methylation on tumour and normal samples. CBioportal was used to analyse copy number mutations in FKBP4 Gene expression and drug sensitivity data were downloaded from the CellMiner database. GO analysis was performed for the high and the low expression of FKBP4 compared with the median level of FKBP4 using clusterProfiler4.0. Results: FKBP4 expression is significantly upregulated in various types of cancers. Cox regression analysis showed that high FKBP4 levels were correlated with poor OS, DSS, DFS, and PFS in most patients with cancer. Methylation of FKBP4 DNA was upregulated in most cancers, and FKBP4 expression is positively associated with transmethylase expression. FKBP4 and its copy were significantly associated with the expression of immune-infiltrating cells, immune checkpoint genes, immune modulators, TMB, MMR, and MSI. FKBP4 expression levels significantly correlated with 16 different drug sensitivities (all p < 0.05). Conclusions: Our pan-cancer bioinformatic analysis revealed a potential mechanism underlying the effects of FKBP4 on the prognosis and progression of various cancers.

Acidosis activates breast cancer ferroptosis through ZFAND5/SLC3A2 signaling axis and elicits M1 macrophage polarization.

Acidosis is involved in multiple pathways in tumor cells and immune cells among the tumor microenvironment (TME). Ferroptosis is a nonapoptotic and iron-dependent form of cell death characterized by accumulation of lipid peroxidation involved in various cancers. The role of ferroptosis in the breast cancer (BC) acidic microenvironment remains unrevealed. Here, we reported that short-term acidosis induced ferroptosis of BC cells in the zinc finger AN1-type domain 5 (ZFAND5)/solute carrier family 3 member 2 (SLC3A2) dependent manner to suppress tumor growth using in silico and multiple biological methods. Mechanistically, we demonstrated that short-term acidosis increased total/lipid reactive oxygen species (ROS) level, decreased glutathione (GSH) level and induced the morphological changes of mitochondria. Specifically, acidosis restrained the protein stability of SLC3A2 by promoting its ubiquitination process. The prognostic analysis showed that higher expression of ZFAND5 and lower expression of SLC3A2 were correlated with longer overall survival of BC patients, respectively. Furthermore, in combination with ferroptosis agonist metformin, short-term acidosis could synergistically inhibit viability and enhance the ferroptosis of BC cells. Meanwhile, by the exploration of immune cells, short-term acidosis also induced M1 macrophage polarization, triggering processes of phagocytosis and ferroptosis in BC cells. This study demonstrated that short-term acidosis induced BC cell ferroptosis through ZFAND5/SLC3A2 signaling axis and promoted phagocytosis and ferroptosis of BC cells with M1 macrophage polarization, which might be a new mechanism for BC therapy.

Naringenin Regulates FKBP4/NR3C1/NRF2 Axis in Autophagy and Proliferation of Breast Cancer and Differentiation and Maturation of Dendritic Cell.

NRF2 is an important regulatory transcription factor involved in tumor immunity and tumorigenesis. In this study, we firstly identified that FKBP4/NR3C1 axis was a novel negative regulator of NRF2 in human breast cancer (BC) cells. The effect of FKBP4 appeared to be at protein level of NRF2 since it could not suppress the expression of NRF2 at mRNA level. Bioinformatics analysis and in vitro experiments further demonstrated that FKBP4 regulated NRF2 via regulating nuclear translocation of NR3C1. We then reported that naringenin, a flavonoid, widely distributed in citrus and tomato, could suppress autophagy and proliferation of BC cells through FKBP4/NR3C1/NRF2 signaling pathway in vitro and in vivo. Naringenin was also found to promote dendritic cell (DC) differentiation and maturation through FKBP4/NR3C1/NRF2 axis. Therefore, our study found that naringenin could induce inhibition of autophagy and cell proliferation in BC cells and enhance DC differentiation and maturation, at least in part, though regulation of FKBP4/NR3C1/NRF2 signaling pathway. Identification of FKBP4/NR3C1/NRF2 axis would provide insights for novel anti-tumor strategy against BC among tumor microenvironment.