gsk-2816126 and Neoplasm-Metastasis

gsk-2816126 has been researched along with Neoplasm-Metastasis* in 3 studies

Other Studies

3 other study(ies) available for gsk-2816126 and Neoplasm-Metastasis

ArticleYear
Epigenetic Silencing of miRNA-34a in Human Cholangiocarcinoma via EZH2 and DNA Methylation: Impact on Regulation of Notch Pathway.
    The American journal of pathology, 2017, Volume: 187, Issue:10

    Aberrant expression and regulation of miRNAs have been implicated in multiple stages of tumorigenic processes. The current study was designed to explore the biological function and epigenetic regulation of miR-34a in human cholangiocarcinoma (CCA). Our data show that the expression of miR-34a is decreased significantly in CCA cells compared with non-neoplastic biliary epithelial cells. Forced overexpression of miR-34a in CCA cells inhibited their proliferation and clonogenic capacity in vitro, and suppressed tumor xenograft growth in severe combined immunodeficiency mice. We identified three key components of the Notch pathway, Notch1, Notch2, and Jagged 1, as direct targets of miR-34a. Our further studies show that down-regulation of miR-34a is caused by Enhancer of zeste homolog 2 (EZH2)-mediated H3 lysine 27 trimethylation as well as DNA methylation. Accordingly, treatment with the EZH2 inhibitor, selective S-adenosyl-methionine-competitive small-molecule (GSK126), or the DNA methylation inhibitor, 5-Aza-2'-deoxycytidine, partially restored miR-34a levels in human CCA cells. Immunohistochemical staining and Western blot analyses showed increased EZH2 expression in human CCA tissues and cell lines. We observed that GSK126 significantly reduced CCA cell growth in vitro and intrahepatic metastasis in vivo. Our findings provide novel evidence that miR-34a expression is silenced epigenetically by EZH2 and DNA methylation, which promotes CCA cell growth through activation of the Notch pathway. Consequently, these signaling cascades may represent potential therapeutic targets for effective treatment of human CCA.

    Topics: Animals; Base Sequence; Bile Duct Neoplasms; Cell Line, Tumor; Cell Proliferation; Cholangiocarcinoma; CpG Islands; DNA Methylation; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Silencing; Histones; Humans; Indoles; Lysine; Male; Mice, Inbred NOD; MicroRNAs; Neoplasm Metastasis; Pyridones; Receptors, Notch; Signal Transduction; Tumor Stem Cell Assay

2017
The abundance of metabolites related to protein methylation correlates with the metastatic capacity of human melanoma xenografts.
    Science advances, 2017, Volume: 3, Issue:11

    Metabolic reprogramming is a major factor in transformation, and particular metabolic phenotypes correlate with oncogenotype, tumor progression, and metastasis. By profiling metabolites in 17 patient-derived xenograft melanoma models, we identified durable metabolomic signatures that correlate with biological features of the tumors. BRAF mutant tumors had metabolomic and metabolic flux features of enhanced glycolysis compared to BRAF wild-type tumors. Tumors that metastasized efficiently from their primary sites had elevated levels of metabolites related to protein methylation, including trimethyllysine (TML). TML levels correlated with histone H3 trimethylation at Lys

    Topics: Animals; Cell Movement; Down-Regulation; Enhancer of Zeste Homolog 2 Protein; Histone-Lysine N-Methyltransferase; Histones; Humans; Indoles; Melanoma; Metabolome; Metabolomics; Methylation; Mice; Mice, Inbred NOD; Neoplasm Metastasis; Principal Component Analysis; Protein Methyltransferases; Proto-Oncogene Proteins B-raf; Pyridones; RNA Interference; RNA, Small Interfering; Transplantation, Heterologous

2017
The novel EZH2 inhibitor, GSK126, suppresses cell migration and angiogenesis via down-regulating VEGF-A.
    Cancer chemotherapy and pharmacology, 2016, Volume: 77, Issue:4

    To explore the effects and mechanisms of GSK126, a novel inhibitor of histone methyltransferase enhancer of zeste homologue 2, on cancer cell migration.. Gastric cancer cell line MGC803 and human lung adenocarcinoma cell line A549 were treated with GSK126 at three doses. Transwell and wound healing assays were conducted to detect cell migration. Human umbilical vein endothelial cells tube formation assay and chick embryo chorioallantoic membrane assay were performed to assess the effects of GSK126 on angiogenesis in vitro and in vivo, respectively. The mRNA level of VEGF-A was detected by quantitative PCR, and the protein levels of VEGF-A were detected both by western blot analysis and immunohistochemistry. Epi-fluorescent intensity was obtained by in vivo imaging.. GSK126 inhibited cell migration in both MGC803 and A549 in a dose-dependent manner, as revealed by transwell and wound healing assays. The effects of GSK 126 were similar to those of gefitinib at the same doses. Moreover, GSK126 at doses of 20 and 50 µM inhibited angiogenesis both in vitro and in vivo. GSK126 reduced both the mRNA and protein expression of VEGF-A in a dose-dependent manner. Finally, in vivo imaging assay revealed that GSK126 at 200 mg/kg significantly inhibited cancer cell migration.. GSK126 inhibits cell migration and angiogenesis in solid tumor cell lines through down-regulation of VEGF-A expression. Thus, it may be considered as a novel anticancer drug candidate for solid tumor.

    Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Cell Movement; Chick Embryo; Enhancer of Zeste Homolog 2 Protein; Humans; Indoles; Male; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Polycomb Repressive Complex 2; Pyridones; Vascular Endothelial Growth Factor A

2016