The transition from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is detrimental to bladder cancer (BLCA) patients. Here, we aimed to study the underlying mechanism of the subtype transition. Gene set variation analysis (GSVA) revealed the epithelial-mesenchymal transition (EMT) signalling pathway with the most positive correlation in this transition. Then, we built a LASSO Cox regression model of an EMT-related gene signature in BLCA. The patients with high risk scores had significantly worse overall survival (OS) and disease-free survival (DFS) than those with low risk scores. The EMT-related gene signature also performed favourably in the accuracy of prognosis and in the subtype survival analysis. Univariate and multivariate Cox regression analyses demonstrated that the EMT-related gene signature, pathological N stage and age were independent prognostic factors for predicting survival in BLCA patients. Furthermore, the predictive nomogram model was able to effectively predict the outcome of BLCA patients by appropriately stratifying the risk score. In conclusion, we developed a novel EMT-related gene signature that has tumour-promoting effects, acts as a negative independent prognostic factor and might facilitate personalized counselling and treatment in BLCA.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.14767

An EMT-related gene signature for the prognosis of human bladder cancer.

In recent years, many studies have shown that histone methylation plays an important role in maintaining the active and silent state of gene expression in human diseases. The Jumonji domain-containing protein D3 (JMJD3), specifically demethylate di- and trimethyl-lysine 27 on histone H3 (H3K27me2/3), has been widely studied in immune diseases, infectious diseases, cancer, developmental diseases, and aging related diseases. We will focus on the recent advances of JMJD3 function in human diseases, and looks ahead to the future of JMJD3 gene research in this review.

/pdf/jmjd3-in-the-regulation-of-human-diseases-3c0nwyahts.pdf

JMJD3 in the regulation of human diseases

The role and prospect of JMJD3 in stem cells and cancer.

Background The histone demethylase LSD1 is a key mediator driving tumorigenesis, which holds potential as a promising therapeutic target. However, treatment with LSD1 inhibitors alone failed to result in complete cancer regression. Methods The synergistic effects of TCP (a LSD1 inhibitor) and GSK-J1 (a JMJD3 inhibitor) against HNSCC were determined in vitro and in preclinical animal models. Genes modulated by chemical agents or siRNAs in HNSCC cells were identified by RNA-seq and further functionally interrogated by bioinformatics approach. Integrative siRNA-mediated gene knockdown, rescue experiment and ChIP-qPCR assays were utilised to characterise the mediators underlying the therapeutic effects conferred by TCP and GSK-J1. Results Treatment with TCP and GSK-J1 impaired cell proliferation, induced apoptosis and senescence in vitro, which were largely recapitulated by simultaneous LSD1 and JMJD3 knockdown. Combinational treatment inhibited tumour growth and progression in vivo. Differentially expressed genes modulated by TCP and GSK-J1 were significantly enriched in cell proliferation, apoptosis and cancer-related pathways. SPP1 was identified as the mediator of synergy underlying the pro-apoptosis effects conferred by TCP and GSK-J1. Co-upregulation of LSD1 and JMJD3 associated with worse prognosis in patients with HNSCC. Conclusions Our findings revealed a novel therapeutic strategy of simultaneous LSD1 and JMJD3 inhibition against HNSCC.

/pdf/therapeutically-targeting-head-and-neck-squamous-cell-4uqk1ratfh.pdf

Therapeutically targeting head and neck squamous cell carcinoma through synergistic inhibition of LSD1 and JMJD3 by TCP and GSK-J1.

Bladder cancer (BLCA) is among the most malignant types of cancer. At present, the prognostic tools available for this disease are insufficient. In the present study, the transcriptome of 1,049 BLCA samples from four datasets from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) were analyzed. By utilizing the RNA-seq data provided by TCGA, a risk score staging system model was built to predict the outcome of patients with BLCA using random forest variable hunting and Cox multivariate regression. A total of 7 genes, including zinc finger protein 230, Bcl2-like 14, AHNAK, transmembrane protein 109, apolipoprotein L2, advanced glycation end-product specific receptor and amine oxidase, copper containing 2 were identified as predicting the survival time of patients with BLCA. The patients with a low risk score had a significantly higher survival rate than those with a high-risk score both in the training and validation datasets. Association analyses between risk score and other clinical information were additionally performed; it was demonstrated that the risk score was significantly associated with pathological stage. A nomogram was plotted to compare risk score and other clinical information. The risk score spanned the greatest range of points, indicating the relative accuracy of risk score. In summary, the risk staging model based on the expression of 7 genes is robust and performs more effectively than other clinical information in predicting a prognosis.

/pdf/a-risk-score-staging-system-based-on-the-expression-of-seven-3wfmmew6as.pdf

A risk score staging system based on the expression of seven genes predicts the outcome of bladder cancer.

Objective UTX and JMJD3 are recently identified histone H3 lysine 27 (H3K27) demethylases. Many studies have shown aberrant H3K27 trimethylation (H3K27me3) levels widely exist in multiple cancers, and that altered H3K27me3 levels are correlated with tumorigenesis and tumor progression. To investigate expression patterns of UTX and JMJD3 genes in renal cell carcinoma (RCC) and bladder cancer and the relationship between gene expression and tumor development. Material and methods Samples were collected from 35 patients with RCC and 21 patients with bladder cancer and qRT-PCR was performed. Results By comparing with adjacent normal tissues, the expression of JMJD3 (10/21 = 47.62%) and UTX (10/21 = 47.62%) were significantly upregulated in bladder cancer tissues and the expression of JMJD3 (15/35 = 42.86%) was significantly downregulated in RCC tissues. Stratified analyses revealed that upregulated expression of JMJD3 was significantly associated with poorly differentiated tumor nuclear grade (p= 0.005) and advanced clinical stage (p= 0.043) in the bladder cancer group, while downregulated expression of JMJD3 was significantly associated with advanced clinical stage (p= 0.045) and poorly differentiated tumor nuclear grade (p= 0.011) in the RCC group. Conclusions These results suggest JMJD3 could be a hallmark and is involved in the development of RCC and bladder cancers. The potential role of H3K27 demethylases as biomarkers needs further investigations.

Different expression patterns of histone H3K27 demethylases in renal cell carcinoma and bladder cancer.

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Different expression patterns of histone H3K27 demethylases in renal cell carcinoma and bladder cancer.