HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer

AIM To investigated the relationships between HER2, c-Jun N-terminal kinase(JNK) and protein kinase B(AKT) with respect to metastatic potential of HER2-positive gastric cancer(GC) cells.METHODS Immunohistochemistry was performed on tissue array slides containing 423 human GC specimens. Using HER2-positve GC cell lines SNU-216 and NCI-N87, HER2 expression was silenced by RNA interference, and the activations of JNK and AKT were suppressed by SP600125 and LY294002, respectively. Transwell assay, Western blot, semi-quantitative reverse transcriptionpolymerase chain reaction and immunofluorescence staining were used in cell culture experiments. RESULTS In GC specimens, HER2, JNK, and AKT activations were positively correlated with each other. In vitro analysis revealed a positive regulatory feedback loop between HER2 and JNK in GC cell lines and the role of JNK as a downstream effector of AKT in the HER2/AKT signaling pathway. JNK inhibition suppressed migratory capacity through reversing EMT and dual inhibition of JNK and AKT induced a more profound effect on cancer cell motility.CONCLUSION HER2, JNK and AKT in human GC specimens are positively associated with each other. JNK and AKT, downstream effectors of HER2, co-operatively contribute to the metastatic potential of HER2-positive GC cells. Thus, targeting of these two molecules in combination with HER2 downregulation may be a good approach to combat HER2-positive GC.

SUV39H1-driven NFATc1 methylation is essential for the c-Cbl-mediated degradation of NFATc1 in an osteoclast lineage

Bone undergoes continuous remodeling by tightly-coordinated actions of bone-resorbing osteoclasts and boneforming osteoblasts.1 Recent studies document that the dysregulation of histone methylation profiles is associated with the progression of osteoclastogenesis.However,the specific epigenetic modifiers are incompletely understood.In this study,we demonstrate an inhibitory role of a variegation 3-9 homolog 1(SUV39H1)in osteoclast formation.

Targeted down-regulation of Hipp1 ameliorates tau-induced deficits in Drosophila melanogaster

Tauopathies,such as Alzheimer's disease(AD),are neurodegenerative diseases characterized by the deposition of neurofibrillary tangles comprising hyperphosphorylated tau protein in the human brain.1 Given that abnormal epigenetic alterations in heterochromatin configuration have been documented in AD patients and transgenic animal models of AD,2 we investigated the roles of novel heterochromatin-associated interactors3 in tauopathies.Using transgenic flies via UAS-Gal4 binary system,we found that knockdown of Hipp1(HP1a and insulator partner protein-1)3 ameliorates.tauR4ow(referred to as"tau"hereafter for simplicity)2-induced locomotion defects,reduced lifespan,and degeneration of brain tissues.Intriguingly,Hipp1 knockdown restored tau-driven aberrant expression of putative insulator targets and aberrant insulator-mediated epigenetic alterations.HIPP1 may have a role as an insulator-binding partner regarding being implicated in tauinduced neurodegeneration.

Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages

Interleukin-10(IL-10)is the most potent anti-inflammatory cytokine in the body and plays an essential role in determining outcomes of many inflammatory diseases.Cellular metabolism is a critical determinant of immune cell function;however,it is currently unclear whether metabolic processes are specifically involved in IL-10 production.In this study,we aimed to find the central metabolic molecule regulating IL-10 production of macrophages,which are the main producers of IL-10.Transcriptomic analysis identified that metabolic changes were predominantly enriched in Kupffer cells at the early inflammatory phase of a mouse endotoxemia model.Among them,pyruvate dehydrogenase kinase(PDK)-dependent acute glycolysis was negatively involved in IL-10 production.Inhibition or knockdown of PDK selectively increased macrophage IL-10 expression.Mechanistically,PDK inhibition increased IL-10 production via profound phosphorylation of adenosine monophosphate(AMP)-activated protein kinase alpha 1(AMPKα1)by restricting glucose uptake in lipopolysaccharide-stimulated macrophages.AMPKα1 consequently activated p38 mitogen-activated protein kinase,c-Jun N-terminal kinase,and cyclic AMP-responsive element-binding protein to regulate IL-10 production.Our study uncovers a previously unknown regulatory mechanism of IL-10 in activated macrophages involving an immunometabolic function of PDK.