gsk-2816126 and Skin-Neoplasms

gsk-2816126 has been researched along with Skin-Neoplasms* in 3 studies

Other Studies

3 other study(ies) available for gsk-2816126 and Skin-Neoplasms

ArticleYear
The Thioredoxin-Interacting Protein TXNIP Is a Putative Tumour Suppressor in Cutaneous T-Cell Lymphoma.
    Dermatology (Basel, Switzerland), 2021, Volume: 237, Issue:2

    The thioredoxin-interacting protein (TXNIP) is involved in cellular metabolism and cell proliferation, and recently, deficient expression of TXNIP has been associated with progression and poor outcome for cancer patients.. To assess TXNIP expression and function in malignant T cells from cutaneous T-cell lymphoma (CTCL).. CTCL-derived malignant (MyLa2059, PB2B) and non-malignant (MyLa1850) cell lines were analysed by Western blotting and qPCR for TXNIP expression. Subsequently, the malignant CTCL cell lines were treated with GSK126 - an inhibitor of enhancer of zeste homolog 2 (EZH2) methyltransferase activity or assessed by bisulphite sequencing for TXNIP promoter methylation. Methylation was also assessed with the demethylating agent 5-azacytidine (5AZA). Finally, TXNIP was overexpressed in the malignant PB2B cell line via plasmid transduction, and the effect of TXNIP was further analysed by flow cytometry.. We report on low expression of TXNIP protein in all cell lines representing different subtypes and stages of CTCL when compared to non-malignant T cells. Epigenetic silencing and other mechanisms were involved in the repression of TXNIP whereas forced expression of TXNIP strongly inhibited proliferation of malignant T cells.. Epigenetic silencing and other as yet unknown mechanisms repress TXNIP expression in malignant T cells. As forced expression of TXNIP inhibits malignant proliferation, we propose that TXNIP is a putative tumour suppressor in CTCL.

    Topics: Carrier Proteins; Cell Line, Tumor; Cell Proliferation; DNA Methylation; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Epigenesis, Genetic; Gene Silencing; Humans; Indoles; Lymphoma, T-Cell, Cutaneous; Promoter Regions, Genetic; Pyridones; Skin Neoplasms

2021
Survival of skin cancer stem cells requires the Ezh2 polycomb group protein.
    Carcinogenesis, 2015, Volume: 36, Issue:7

    Polycomb group proteins, including Ezh2, are important candidate stem cell maintenance proteins in epidermal squamous cell carcinoma. We previously showed that epidermal cancer stem cells (ECS cells) represent a minority of cells in tumors, are highly enriched in Ezh2 and drive aggressive tumor formation. We now show that Ezh2 is required for ECS cell survival, migration, invasion and tumor formation and that this is associated with increased histone H3 trimethylation on lysine 27, a mark of Ezh2 action. We also show that Ezh2 knockdown or treatment with Ezh2 inhibitors, GSK126 or EPZ-6438, reduces Ezh2 level and activity, leading to reduced ECS cell spheroid formation, migration, invasion and tumor growth. These studies indicate that epidermal squamous cell carcinoma cells contain a subpopulation of cancer stem (tumor-initiating) cells that are enriched in Ezh2, that Ezh2 is required for optimal ECS cell survival and tumor formation and that treatment with Ezh2 inhibitors may be a strategy for reducing ECS cell survival and suppressing tumor formation.

    Topics: Animals; Benzamides; Biphenyl Compounds; Cell Line, Tumor; Cell Movement; Cell Survival; Enhancer of Zeste Homolog 2 Protein; Gene Knockdown Techniques; Humans; Indoles; Mice, Inbred NOD; Morpholines; Neoplastic Stem Cells; Polycomb Repressive Complex 2; Pyridones; Skin Neoplasms; Xenograft Model Antitumor Assays

2015
Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes.
    Oncotarget, 2015, Sep-29, Volume: 6, Issue:29

    The epigenetic modifier EZH2 is part of the polycomb repressive complex that suppresses gene expression via histone methylation. Activating mutations in EZH2 are found in a subset of melanoma that contributes to disease progression by inactivating tumor suppressor genes. In this study we have targeted EZH2 with a specific inhibitor (GSK126) or depleted EZH2 protein by stable shRNA knockdown. We show that inhibition of EZH2 has potent effects on the growth of both wild-type and EZH2 mutant human melanoma in vitro particularly in cell lines harboring the EZH2Y646 activating mutation. This was associated with cell cycle arrest, reduced proliferative capacity in both 2D and 3D culture systems, and induction of apoptosis. The latter was caspase independent and mediated by the release of apoptosis inducing factor (AIFM1) from mitochondria. Gene expression arrays showed that several well characterized tumor suppressor genes were reactivated by EZH2 inhibition. This included activating transcription factor 3 (ATF3) that was validated as an EZH2 target gene by ChIP-qPCR. These results emphasize a critical role for EZH2 in the proliferation and viability of melanoma and highlight the potential for targeted therapy against EZH2 in treatment of patients with melanoma.

    Topics: Activating Transcription Factor 3; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Progression; Enhancer of Zeste Homolog 2 Protein; Epigenomics; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, Tumor Suppressor; Genotype; Histones; Humans; Indoles; Inhibitory Concentration 50; Melanoma; Mutation; Polycomb Repressive Complex 2; Pyridones; Skin Neoplasms; Up-Regulation

2015