FKBP11 upregulation promotes proliferation and migration in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths world over. Early diagnosis and effective treatment monitoring significantly improves patients' outcomes. FKBP11 gene is highly expressed in HCC and could play a role in its development, early diagnosis and treatment. OBJECTIVE: This study aimed to evaluate the expression of FKBP11 in HCC, its correlation with patients' clinical characteristics and potential role in HCC development. METHODS: Expression was determined by bioinformatics analysis, quantitative real-time PCR, western blot, and immunohistochemistry. CCK-8, Transwell and wound healing assays were used to investigate involvement in HCC development. RESULTS: FKBP11 was significantly upregulated in HCC cells, tissues and blood (all p< 0.001). Its receiver operator characteristic (ROC) curve had an AUC of 0.864 (95% CI: 0.823-0.904), at a sensitivity of 0.86 and specificity of 0.78 indicating a good diagnostic potential in HCC. Its expression was markedly reduced after surgery (p< 0.0001), indicating a potential application in HCC treatment follow-up. Knockdown of FKBP11 in HCC cells attenuated proliferation and migration, suggesting a possible role in HCC pathogenesis. CONCLUSION: This study thus found that FKBP11 is upregulated in HCC, and the upregulation promotes HCC development. FKBP11 levels are significantly reduced post-surgery and could be a potential diagnostic and prognostic marker for HCC.

FKBP11 improves the malignant property of osteosarcoma cells and acts as a prognostic factor of osteosarcoma.

BACKGROUND: Osteosarcoma has become the most common bone malignancy in adolescents. Although the clinical treatment of osteosarcoma has advanced considerably in recent years, the 5-year survival rate has not improved significantly. Recently, many studies have shown that mRNA has unique advantages as a target for drug therapy. Therefore, this study aimed to identify a new prognostic factor and provide a new target for the treatment of osteosarcoma to improve the prognosis of patients. METHODS AND RESULTS: We selected prognostic genes that are closely associated with osteosarcoma clinical features by obtaining osteosarcoma patient information from the GTEx and TARGET databases, and then we developed a risk model. We detected the expression of FKBP11 in osteosarcoma by qRT-PCR, western blotting, and immunohistochemistry and performed CCK-8, Transwell, colony formation, and flow cytometry assays to reveal the regulatory role of FKBP11. We found that FKBP11 was highly expressed in osteosarcoma; silencing FKBP11 expression suppressed the invasion and migration of osteosarcoma cells, slowed cell proliferation, and promoted apoptosis. We also found that silencing the expression of FKBP11 led to inhibition of MEK/ERK phosphorylation. CONCLUSIONS: In conclusion, we validated that the prognostic factor FKBP11 is closely associated with osteosarcoma. Additionally, we identified a novel mechanism by which FKBP11 ameliorates the malignant properties of osteosarcoma cells through the MAPK pathway and serves as a prognostic factor in osteosarcoma. This study provides a new method for the treatment of osteosarcoma.

FKBP11 rewires UPR signaling to promote glucose homeostasis in type 2 diabetes and obesity.

Chronic endoplasmic reticulum (ER) stress and sustained activation of unfolded protein response (UPR) signaling contribute to the development of type 2 diabetes in obesity. UPR signaling is a complex signaling pathway, which is still being explored in many different cellular processes. Here, we demonstrate that FK506-binding protein 11 (FKBP11), which is transcriptionally regulated by XBP1s, is severely reduced in the livers of obese mice. Restoring hepatic FKBP11 expression in obese mice initiates an atypical UPR signaling pathway marked by rewiring of PERK signaling toward NRF2, away from the eIF2α-ATF4 axis of the UPR. This alteration in UPR signaling establishes glucose homeostasis without changing hepatic ER stress, food consumption, or body weight. We conclude that ER stress during obesity can be beneficially rewired to promote glucose homeostasis. These findings may uncover possible new avenues in the development of novel approaches to treat diseases marked by ER stress.

FKBP11 promotes cell proliferation and tumorigenesis via p53-related pathways in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the causes of cancer-related death worldwide. The abnormal proliferation ability of OSCC has become one of the major reasons for its poor prognosis. FK-506 binding protein 11 (FKBP11) is abnormally expressed in malignant tumors and affects many biological processes. The purpose of this study is to investigate the effect of FKBP11 on cell proliferation in OSCC and explore the possible regulatory mechanism. The expression of FKBP11 was detected by western blotting (WB) and/or real-time PCR in OSCC and paracancerous normal tissues in tongue squamous cell carcinoma (TSCC) cell lines, revealing high expression in OSCC and CAL-27 cells. Furthermore, FKBP11 knockdown inhibited the proliferation of CAL-27 cells by CCK-8 and colony formation assays. G2/M arrest and induction of apoptosis were observed using flow cytometry, Hoechst 33258 and Calcein-AM/PI staining, accompanied by changes in some cell cycle- and apoptosis-related proteins, including CDK1, Cyclin B1, p21, p27, p53, Bax, Bcl-2 and Caspase-3. Additionally, the expression of these proteins can be reversed by the use of pifithrin-α (PFT-α), a p53 inhibitor. An in vivo xenograft model further confirmed that FKBP11 enhanced OSCC progression. In conclusion, FKBP11 could promote cell proliferation by regulating G2/M phase and apoptosis via the p53/p21/p27 and p53/Bcl-2/Bax pathways, respectively, which suggests that it may be a new candidate target for the treatment of OSCC.

Spliced X-box Binding Protein 1 Stimulates Adaptive Growth Through Activation of mTOR.

BACKGROUND: The unfolded protein response plays versatile roles in physiology and pathophysiology. Its connection to cell growth, however, remains elusive. Here, we sought to define the role of unfolded protein response in the regulation of cardiomyocyte growth in the heart. METHODS: We used both gain- and loss-of-function approaches to genetically manipulate XBP1s (spliced X-box binding protein 1), the most conserved signaling branch of the unfolded protein response, in the heart. In addition, primary cardiomyocyte culture was used to address the role of XBP1s in cell growth in a cell-autonomous manner. RESULTS: We found that XBP1s expression is reduced in both human and rodent cardiac tissues under heart failure. Furthermore, deficiency of XBP1s leads to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac-restricted overexpression of XBP1s prevents the development of cardiac dysfunction. Mechanistically, we found that XBP1s stimulates adaptive cardiac growth through activation of the mechanistic target of rapamycin signaling, which is mediated via FKBP11 (FK506-binding protein 11), a novel transcriptional target of XBP1s. Moreover, silencing of FKBP11 significantly diminishes XBP1s-induced mechanistic target of rapamycin activation and adaptive cell growth. CONCLUSIONS: Our results reveal a critical role of the XBP1s-FKBP11-mechanistic target of rapamycin axis in coupling of the unfolded protein response and cardiac cell growth regulation.

Weighted Gene Co-expression Network Analysis Identifies FKBP11 as a Key Regulator in Acute Aortic Dissection through a NF-kB Dependent Pathway.

Acute aortic dissection (AAD) is a life-threatening disease. Despite the higher risk of mortality, currently there are no effective therapies that can ameliorate AAD development or progression. Identification of meaningful clusters of co-expressed genes or representative biomarkers for AAD may help to identify new pathomechanisms and foster development of new therapies. To this end, we performed a weighted gene co-expression network analysis (WGCNA) and calculated module-trait correlations based on a public microarray dataset (GSE 52093) and discovered 9 modules were found to be related to AAD. The module which has the strongest positive correlation with AAD was further analyzed and the top 10 hub genes SLC20A1, GINS2, CNN1, FAM198B, MAD2L2, UBE2T, FKBP11, SLMAP, CCDC34, and GALK1 were identified. Furthermore, we validated the data by qRT-PCR in an independent sample set originated from our study center. Overall, the qRT-PCR results were consistent with the results of the microarray analysis. Intriguingly, the highest change was found for FKBP11, a protein belongs to the FKBP family of peptidyl-prolyl cis/trans isomerases, which catalyze the folding of proline-containing polypeptides. In congruent with the gene expression analysis, FKBP11 expression was induced in cultured endothelial cells by angiotensin II treatment and endothelium of the dissected aorta. More importantly we show that FKBP11 provokes inflammation in endothelial cells by interacting with NF-kB p65 subunit, resulting in pro-inflammatory cytokines production. Accordingly, siRNA mediated knockdown of FKBP11 in cultured endothelial cells suppressed angiotensin II induced monocyte transmigration through the endothelial monolayer. Based on these data, we hypothesize that pro-inflammatory cytokines elicited by FKBP11 overexpression in the endothelium under AAD condition could facilitate transendothelial migration of the circulating monocytes into the aorta, where they differentiate into active macrophages and secrete MMPs and other extracellular matrix (ECM) degrading proteins, contributing to sustained inflammation and AAD. Taken together, our data identify important role of FKBP11 which can serve as biomarker and/or therapeutic target for AAD.

Overexpression of Fkbp11, a feature of lupus B cells, leads to B cell tolerance breakdown and initiates plasma cell differentiation.

Systemic Lupus Erythematosus (SLE) is a severe systemic autoimmune disease, characterized by multi-organ damages, triggered by an autoantibody-mediated inflammation, and with a complex genetic influence. It is today accepted that adult SLE arises from the building up of many subtle gene variations, each one adding a new brick on the SLE susceptibility and contributing to a phenotypic trait to the disease. One of the ways to find these gene variations consists in comprehensive analysis of gene expression variation in a precise cell type, which can constitute a good complementary strategy to genome wide association studies. Using this strategy, and considering the central role of B cells in SLE, we analyzed the B cell transcriptome of quiescent SLE patients, and identified an overexpression of FKBP11, coding for a cytoplasmic putative peptidyl-prolyl cis/trans isomerase and chaperone enzyme. To understand the consequences of FKBP11 overexpression on B cell function and on autoimmunity's development, we created lentiviral transgenic mice reproducing this gene expression variation. We showed that high expression of Fkbp11 reproduces by itself two phenotypic traits of SLE in mice: breakdown of B cell tolerance against DNA and initiation of plasma cell differentiation by acting upstream of Pax5 master regulator gene.

Identification of FKBP11 as a biomarker for hepatocellular carcinoma.

BACKGROUND: Glycine N-methyltransferase (GNMT) is a tumor suppressor of hepatocellular carcinoma (HCC). High proportions of GNMT knockout mice developed HCC. We previously identified a potential novel marker from Gnmt knockout mice, FK506 binding protein 11 (FKBP11). Here, we determined the clinical usefulness of FKBP11. PATIENTS AND METHODS: FKBP11 expression levels were analyzed in 123 paired tumor and tumor-adjacent non-tumorous (TA) tissue samples from patients with HCC and in 29 benign liver samples from patients with hemangioma using quantitative real-time polymerase-chain-reaction. RESULTS: FKBP11 was expressed at a higher level in tumor tissues compared to TA tissues (p<0.01). Moreover, we observed a significantly higher level of FKBP11 in TA tissues than in benign liver samples (p<0.01). Interestingly, expression of FKBP11 was higher in hepatitis viral-infected TA and benign tissues than in samples without viral etiology (p<0.05). CONCLUSION: These results suggest a progressively elevated expression of FKBP11 during the development of HCC and FKBP11 has the potential to be an early marker for HCC.