gsk-2816126 and Lymphoma--T-Cell--Cutaneous

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