Breast cancer is the most common malignancy for women worldwide, while Triple Negative Breast Cancer (TNBC) accounts for 20% in all patients. Compared with estrogen receptor positive breast cancer, which could be effectively controlled via endocrine therapy, TNBC is more aggressive and worse in prognosis. It is therefore urgent and necessary to develop a novel therapeutic strategy for TNBC treatment. Recent studies identified Hippo signaling is highly activated in TNBC, which could be a driving pathway for TNBC progression. In our study, we determine RNF187 as a negative regulator for Hippo signaling activation. RNF187 depletion significantly decreases cell migration and invasion capacity in TNBC. These effects could be rescued by further YAP depletion. Depletion of RNF187 increases the YAP protein level and Hippo signaling target genes, such as CTGF and CYR61 in TNBC. Immuno-precipitation assay shows that RNF187 associates with YAP, promoting its degradation possibly via inducing YAP K48-dependent poly-ubiquitination. Interestingly, Our clinical data reveals that RNF187 reversely correlates with YAP protein level and Hippo target genes. RNF187 tends to correlate with good prognosis in TNBC patients. Our study provides evidence to establish a proteolytic mechanism in regulation Hippo signaling activation in TNBC.

Background: The Hippo pathway functions as a tumor suppressor pathway in human cancers, while dysfunction of the Hippo pathway is frequently observed in malignancies. Although YAP/TAZ activity is tightly controlled by the phosphorylation cascade of the MST-LATS-YAP/TAZ axis, it is still unclear why the YAP/TAZ proteins are activated in human cancers despite Hippo pathway activation. Recent studies have suggested that in addition to phosphorylation, several other posttranslational modifications, including ubiquitination, also play critical roles in modulating TAZ function.Methods: We used several gastric cancer cell lines and performed western blot analysis, real-time PCR, immunoprecipitation assays, and in vitro ubiquitination assays and established a xenograft mouse model.Results: Here, by screening a DUB (deubiquitinase) siRNA library, we discovered that DUB1 functions as a critical modulator that facilitates gastric cancer stemness and progression by deubiquitinating and activating the TAZ protein. We also found that DUB1 expression was elevated in gastric cancer and that elevated DUB1 expression correlated with TAZ activation and poor survival. DUB1 associates with the TAZ protein and deubiquitinates TAZ at several lysine residues, which subsequently stabilizes TAZ and facilitates its function.Conclusions: Our study revealed a novel deubiquitinase in the Hippo/TAZ axis and identified one possible therapeutic target for Hippo-driven gastric cancer.

Lung adenocarcinoma (LUAD) is one of the most universal types of cancer all over the world and its morbidity continues to rise year by year. Growing evidence has demonstrated that endoplasmic reticulum stress is highly activated in cancer cells and plays a key role in regulating the fate of cancer cells. However, the role and mechanism of endoplasmic reticulum stress in lung adenocarcinoma genesis and development remains unclear. In this research, we developed a prognostic model to predict the overall survival of patients with LUAD utilizing endoplasmic reticulum stress-related genes and screened out potential small molecular compounds, which could assist the clinician in making accurate decisions and better treat LUAD patients. Firstly, we downloaded 419 endoplasmic reticulum stress-related genes (ERSRGs) from Molecular Signatures Database (MSigDB). Secondly, we obtained information about the transcriptome profiling and corresponding clinical data of 59 normal samples and 535 lung adenocarcinoma samples from The Cancer Genome Atlas (TCGA) database. Next, we used the DESeq2 package to identify differentially expressed genes related to endoplasmic reticulum stress. We performed univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis to establish a prognostic model for LUAD patients based on ERSRGs. Then, we carried out univariate and multivariate independent prognostic analysis of endoplasmic reticulum stress-related gene (ERSRG) score and some clinical traits of lung adenocarcinoma. Additionally, we developed a clinically applicable nomogram for predicting survival for LUAD patients over one, three, and five years. Moreover, we carried out a drug sensitivity analysis to identify novel small molecule compounds for LUAD treatment. Finally, we examined the tumor microenvironment (TME) and immune cell infiltrating analysis to explore the interactions between immune and cancer cells. 142 differentially expressed ERSRGs were identified by using the DESeq2 package. A prognostic model was built based on 7 differentially expressed ERSRGs after performing univariate Cox regression, LASSO regression, and multivariate Cox regression analysis. According to the results of univariate and multivariate independent prognostic analysis, we found ERSRG score can be used as an independent prognostic maker. Using the Kaplan–Meier curves, we found low-risk patients had higher survival probability than high-risk patients in both training set and test set. A nomogram was drawn to predict 1-, 3-, and 5-year survival probability. The calibration curves explained good performance of the model for the prediction of survival. Phenformin, OSU-03012, GSK-650394 and KIN001-135 were identified as the drugs most likely to provide important information to clinicians about the treatment of LUAD patients. A prognostic prediction model was established based on 7 differentially expressed ERSRGs (PDX1, IGFBP1, DDIT4, PPP1R3G, CFTR, DERL3 and NUPR1), which could effectively predict the prognosis of LUAD patients and give a reference for clinical doctors to help LUAD patients to make better treatment tactics. Based on the 4 small molecule compounds (Phenformin, OSU-03012, GSK-650394 and KIN001-135) we discovered, targeting endoplasmic reticulum stress-related genes may also be a therapeutic approach for LUAD patients.

Background: Acute sprint exercise is a time-efficient physical activity that improves cardiorespiratory fitness in younger and middle-aged adults. Growing evidence has demonstrated that acute sprint exercise provides equal to or superior health benefits compared with moderate-intensity continuous training, which will dramatically increase aerobic capacity, insulin sensitivity, and muscle capillarization. Although the beneficial effects of acute sprint exercise are well documented, the mechanisms behind how acute sprint exercise prevents disease and benefits health are less understood.Method: We obtained differentially expressed genes in muscle (vastus lateralis) from men and women before and after an acute sprint exercise. Then, we identified hub genes from the protein–protein interaction (PPI) network of differentially expressed genes (DEGs) and key transcription factors in men and women related to acute sprint exercise. Finally, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses are performed on DEGs and sex-biased genes, respectively.Results: First, we identified 127 sexually dimorphic genes in men (90 upregulated and 37 downregulated) and 75 genes in women (90 upregulated and 37 downregulated) in response to acute sprint exercise. Second, CEBPB, SMAD3, and CDKN1A are identified as the top three hub genes related to men-biased genes. Accordingly, the top three hub genes related to women-biased genes are JUN, ACTB, and SMAD7. In addition, CLOCK, ZNF217, and KDM2B are the top three enriched transcriptional factors in men-biased genes, while XLR, SOX2, JUND, and KLF4 are transcription factors enriched most in women-biased genes. Furthermore, based on GO and KEGG enrichment analyses, we identified potential key pathways in regulating the exercise-related response in men and women, respectively.Conclusion: In this study, we found the difference in gene expression and enrichment pathways in muscle in men and women in response to acute sprint exercise. These results will shed new light on the mechanism underlying sex-based differences in skeletal muscle remodeling and metabolism related to acute sprint exercise, which may illustrate the mechanisms behind how acute sprint exercise prevents disease and benefits health.

Construction of a novel lncRNA-miRNA-mRNA competing endogenous RNA network in muscle in response to exercise training