Breast cancer is one of the most commonly diagnosed malignancies worldwide, while the triple negative breast cancer (TNBC) is the most aggressive and virulent subtype in breast cancers. Compared with luminal type breast cancers, which could be well controlled by endocrine treatment, TNBC is worse in prognosis and lack of effective targeted therapy. Thus, it would be interesting and meaningful to identify novel therapeutic targets for TNBC treatments. Recent genomic data showed the activation of Hippo/YAP signaling in TNBC, indicating its critical roles in TNBC carcinogenesis and cancer progression. Hippo/YAP signaling could subject to several kinds of protein modifications, including ubiquitination and phosphorylation. Quite a few studies have demonstrated these modifications, which controlled YAP protein stability and turnover, played critical role in Hippo signaling activation In our current study, we identified ZNF213 as a negative modifier for Hippo/YAP axis. ZNF213 depletion promoted TNBC cell migration and invasion, which could be rescued by further YAP silencing. ZNF213 knocking down facilitated YAP protein stability and Hippo target gene expression, including CTGF and CYR61. Further mechanism studies demonstrated that ZNF213 associated with YAP and facilitated YAP K48‐linked poly‐ubiquitination at several YAP lysine sites (K252, K254, K321 and K497). Besides, the clinical data showed that ZNF213 negatively correlated with YAP protein level and Hippo target gene expression in TNBC samples. ZNF213 expression correlated with good prognosis in TNBC patients. Our data provided novel insights in YAP proteolytic regulation and TNBC progression.

Breast cancer is the most common malignancy in women on a global scale. It can generally be divided into four main categories, of which estrogen receptor ER-positive breast cancer accounts for most breast cancer cases. RBCK1 protein is an E3 ubiquitin ligase containing the UBL, NZF, and RBR domains. It is well known to exhibit abnormal expression in breast tumors, making it a valuable diagnostic marker and drug target. Additionally, studies have confirmed that in breast cancer, about 25 to 40% of tumors appear as visible hypoxic regions, while in hypoxia, tumor cells can activate the hypoxia-inducing factor HIF1 pathway and widely activate the expression of downstream genes. Previous studies have confirmed that in the hypoxic environment of tumors, HIF1α promotes the remodeling of extracellular matrix, induces the recruitment of tumor-associated macrophages (TAM) and immunosuppression of allogeneic tumors, thereby influencing tumor recurrence and metastasis. This research aims to identify RBCK1 as an important regulator of HIF1α signaling pathway. Targeted therapy with RBCK1 could be a promising treatment strategy for ER-positive breast cancer.

Background: Dysregulated glucose metabolism in the brain is considered to be one of the key causes of Alzheimer’s disease (AD). Abnormal glucose uptake in AD is tightly associated with decreased levels of glucose transporter 1 (GLUT1) and GLUT3 in the brain, but the underlying mechanisms remain unclear. Objective: We aimed to explore the cause and mechanism of impaired glucose uptake in AD. Methods: N2a/WT and N2a/APP695swe cells were cultured in vitro, and cellular glucose uptake and ATP content, as well as the expression of GLUT1, GLUT3, and PI3K/Akt pathway members, were detected. Intracellular reactive oxygen species (ROS) levels were detected by flow cytometry. After treatment with the ROS scavenger N-acetyl-L-cysteine (NAC), the above indicators were detected again. Results: GLUT1 expression was significantly decreased (p = 0.0138) in N2a/APP695swe cells, while GLUT3 expression was no statistical difference (p >  0.05). After NAC treatment, PI3K and Akt phosphorylation levels, GLUT1 expression, glucose uptake and ATP levels were remarkably increased (p = 0.0006, p = 0.0008, p = 0.0009, p = 0.0001, p = 0.0013), while Aβ levels were significantly decreased (p = 0.0058, p = 0.0066). After addition of the PI3K inhibitor LY29004, GLUT1 expression was reduced (p = 0.0008), and Aβ levels were increased (p = 0.0009, p = 0.0117). In addition, increases in glucose uptake and ATP levels induced by the Akt activator SC79 were hindered by the GLUT1 inhibitor WZB117 (p = 0.0002, p = 0.0005). Aβ levels were decreased after SC79 treatment and increased after WZB117 treatment (p = 0.0212, p = 0.0006). Conclusion: Taken together, scavenging of ROS prevents from Aβ deposition via activation of the PI3K/Akt/GLUT1 pathway, and improved the impaired glucose uptake in N2a/APP695swe cells.

BackgroundPyroptosis has been demonstrated to be an inflammatory form of programmed cell death recently. However, the expression of pyroptosis-related genes (PRGs) in colon adenocarcinoma (COAD) and their correlations with prognosis remain unclear.MethodsData of COAD patients were obtained from The Cancer Genome Atlas (TCGA) database to screen differentially expressed genes (DEGs). Univariate Cox regression analysis and the LASSO Cox regression analysis were applied to construct a gene signature. All COAD patients in TCGA cohort were separated into low-risk subgroup or high-risk subgroup via the risk score. Kaplan–Meier survival analysis and receiver operator characteristic (ROC) curves were adopted to assess its prognostic efficiency. COAD data from the GSE17537 datasets was used for validation. A prognostic nomogram was established to predict individual survival. The correlation between PRGs and immune cell infiltration in COAD was verified based on TIMER database. CIBERSORT analysis was utilized on risk subgroup as defined by model. The protein and mRNA expression level of PRGs were verified by HPA database and qPCR.ResultsA total of 51 differentially expressed PRGs were identified in TCGA cohort. Through univariate Cox regression analysis and LASSO Cox regression analysis, a prognostic model containing 7 PRGs was constructed. Kaplan–Meier survival analysis indicated that patients in the low-risk subgroup exhibited better prognosis compared to those in the high-risk subgroup. Additionally, the area under the curve (AUC) of ROC is 0.60, 0.63, and 0.73 for 1-, 3-, and 5-year survival in TCGA cohort and 0.63, 0.65, and 0.64 in validation set. TIMER database showed a strong correlation between 7 PRGs and tumor microenvironment in COAD. Moreover, CIBERSORT showed significant differences in the infiltration of plasma cells, M0 macrophages, resting dendritic cells, and eosinophils between low-risk subgroup and high-risk subgroup. HPA database showed that protein expression level of SDHB, GZMA, BTK, EEF2K, and NR1H2 was higher in normal tissues. And the transcriptional level of CASP5, BTK, SDHB, GZMA, and RIPK3 was high in normal tissues.ConclusionsOur study identified a novel PRGs signature that could be used to predict the prognosis of COAD patients, which might provide a new therapeutic target for the treatment of COAD patients.