STAC1 is required for glioblastoma cell invasion and survival.

Glioblastoma Multiforme (GBM) is a highly malignant brain tumor with poor prognosis. Understanding the molecular mechanisms driving GBM tumorigenesis is crucial for developing effective therapeutic strategies. This study investigates the role of STAC1, a gene belonging to the SH3 and cysteine-rich domain family, in glioblastoma cell invasion and survival. Computational analyses of patient samples reveal that STAC1 expression is elevated in GBM tissues, and higher STAC1 expression is associated with lower overall survival rates. Consistently, we find that overexpression of STAC1 in glioblastoma cells enhances invasion, while knockdown of STAC1 reduces invasion and the expression of genes associated with epithelial-to-mesenchymal transition (EMT). STAC1 depletion also induces apoptosis in glioblastoma cells. Furthermore, we show that STAC1 regulates AKT and calcium channel signaling in glioblastoma cells. Collectively, our study provides valuable insights into the pathogenic roles of STAC1 in GBM and highlights its potential as a promising target for the treatment of high-grade glioblastoma.

The CRHR1/CREB/REST signaling cascade regulates mammalian embryonic neural stem cell properties.

Growing evidence suggests that the corticotropin-releasing hormone (CRH) signaling pathway, mainly known as a critical initiator of humoral stress responses, has a role in normal neuronal physiology. However, despite the evidence of CRH receptor (CRHR) expression in the embryonic ventricular zone, the exact functions of CRH signaling in embryonic brain development have not yet been fully determined. In this study, we show that CRHR1 is required for the maintenance of neural stem cell properties, as assessed by in vitro neurosphere assays and cell distribution in the embryonic cortical layers following in utero electroporation. Identifying the underlying molecular mechanisms of CRHR1 action, we find that CRHR1 functions are accomplished through the increasing expression of the master transcription factor REST. Furthermore, luciferase reporter and chromatin immunoprecipitation assays reveal that CRHR1-induced CREB activity is responsible for increased REST expression at the transcriptional level. Taken together, these findings indicate that the CRHR1/CREB/REST signaling cascade plays an important role downstream of CRH in the regulation of neural stem cells during embryonic brain development.

YAP inhibits HCMV replication by impairing STING-mediated nuclear transport of the viral genome.

YES-associated protein (YAP), a critical actor of the mammalian Hippo signaling pathway involved in diverse biological events, has gained increased recognition as a cellular factor regulated by viral infections, but very few studies have investigated their relationship vice versa. In this study, we show that YAP impairs HCMV replication as assessed by viral gene expression analysis and progeny assays, and that this inhibition occurs at the immediate-early stages of the viral life cycle, at the latest. Using YAP mutants lacking key functional domains and shRNA against TEAD, we show that the inhibitory effects of YAP on HCMV replication are nuclear localization- and TEAD cofactor-dependent. Quantitative real-time PCR (qPCR) and subcellular fractionation analyses reveal that YAP does not interfere with the viral entry process but inhibits transport of the HCMV genome into the nucleus. Most importantly, we show that the expression of stimulator of interferon genes (STING), recently identified as an important component for nuclear delivery of the herpesvirus genome, is severely downregulated by YAP at the level of gene transcription. The functional importance of STING is further confirmed by the observation that STING expression restores YAP-attenuated nuclear transport of the HCMV genome, viral gene expression, and progeny virus production. We also show that HCMV-upregulated YAP reduces expression of STING. Taken together, these findings indicate that YAP possesses both direct and indirect regulatory roles in HCMV replication at different infection stages.

Gamma secretase inhibition impairs HCMV replication by reduction of immediate early gene expression at the transcriptional level.

Due to diverse pathogenic potentials, there is a growing need for anti-HCMV agents. In this study, we show that treatment with DAPT, a γ-secretase inhibitor (GSI), impairs HCMV replication as assessed by a progeny assay based on immunostaining. This effect is not limited to DAPT because other GSIs with different structures and distinct mechanisms of action also exhibit a similar level of inhibitory effects on HCMV viral production, indicating that γ-secretase activity is required for efficient HCMV replication. Western blot and qPCR analyses reveal that DAPT does not interfere with the viral entry process, but reduces expression of the immediate early protein IE1 at the transcriptional level. Furthermore, we exclude the possible involvement of Notch signaling pathway during HCMV replication by showing that expression of the dominant-negative form of MAML1, which disrupts the transactivational ability of Notch intracellular domain (NICD), does not reduce viral particle formation, and that NICD cannot rescue the DAPT-treated outcomes. Taken together, these findings indicate that γ-secretase activity plays an important role in a key step of the HCMV life cycle and γ-secretase inhibition could potentially be used as a novel preventive and therapeutic strategy against HCMV infection and HCMV-related diseases.

YAP Enhances FGF2-Dependent Neural Stem Cell Proliferation by Induction of FGF Receptor Expression.

The Hippo signaling pathway regulates cell proliferation and organ growth, and its activation is mainly reflected by the phosphorylation levels of Yes-associated protein (YAP). In this study, we show that YAP facilitates embryonic neural stem cell proliferation by elevating their responsiveness to fibroblast growth factor 2 (FGF2), one of the major growth factors for neural stem cells, in vivo as well as in vitro. Western blot and quantitative real-time PCR analyses revealed that expression of the FGF receptors (FGFRs) FGFR1 to FGFR4 were greatly increased by YAP expression upon FGF2 treatment, followed by upregulation of the mitogen-activated protein kinase and protein kinase B signaling pathways. Furthermore, as assessed by quantitative real-time PCR analyses, YAP-induced FGFR expression was found to be TEA domain transcription factor (TEAD)-independent, and transcriptional coactivator with PDZ-binding motif, the other homolog of Yorki in the Drosophila Hippo signaling pathway, was found to possess similar activity to YAP. Finally, adjustment of FGFR signaling activity in the YAP-expressing cells to control levels efficiently offset the cell proliferative effects of YAP, suggesting that the increased proliferation of YAP-expressing neural stem cells was mainly attributable to enhanced FGFR signaling. Our data indicate that YAP plays an important role in neural stem cell regulation by elevating FGFR expression, subsequently leading to enhanced cell proliferation.