Epigenetic Drugs Can Stimulate Metastasis through Enhanced Expression of the Pro-Metastatic Ezrin Gene

Ezrin has been reported to be upregulated in many tumors and to participate in metastatic progression. No study has addressed epigenetic modification in the regulation of Ezrin gene expression, the importance of which is unknown. Here, we report that highly metastatic rhabdomyosarcoma (RMS) cells with high levels of Ezrin have elevated acetyl-H3-K9 and tri-methyl-H3-K4 as well as reduced DNA methylation at the Ezrin gene promoter. Conversely, poorly metastatic RMS cells with low levels of Ezrin have reduced acetyl-H3-K9 and elevated methylation. Thus epigenetic covalent modifications to histones within nucleosomes of the Ezrin gene promoter are linked to Ezrin expression, which in fact can be regulated by epigenetic mechanisms. Notably, treatment with histone deacetylase (HDAC) inhibitors or DNA demethylating agents could restore Ezrin expression and stimulate the metastatic potential of poorly metastatic RMS cells characterized by low Ezrin levels. However, the ability of epigenetic drugs to stimulate metastasis in RMS cells was inhibited by expression of an Ezrin-specific shRNA. Our data demonstrate the potential risk associated with clinical application of broadly acting covalent epigenetic modifiers, and highlight the value of combination therapies that include agents specifically targeting potent pro-metastatic genes

Aberrant DNA Methylation of Matrix Remodeling and Cell Adhesion Related Genes in Pterygium

10.1371/journal.pone.0014687PLoS ONE62

Transketolase catalysed upgrading of l-arabinose: the one-step stereoselective synthesis of l-gluco-heptulose

Conversion of biomass using biocatalysis is likely to become a technology that contributes significantly to the future production of chemical building blocks, materials and transport fuels. Here the synthesis of a value-added chemical from L-arabinose, a major component of the carbohydrates in sugar beet pulp (SBP), in a concise and sustainable manner has been investigated. Biocatalytic conversions using transketolase variants have been developed for the efficient, scalable synthesis of a rare naturally occurring ketoheptose, L-gluco-heptulose, from L-arabinose. New active E. coli TK mutants that readily accept L-arabinose were identified using a versatile colorimetric screening assay and the reaction was performed on a preparative scale

Structural and functional insights into asymmetric enzymatic dehydration of alkenols

The asymmetric dehydration of alcohols is an important process for the direct synthesis of alkenes. We report the structure and substrate specificity of the bifunctional linalool dehydratase isomerase (LinD) from the bacterium Castellaniella defragrans that catalyzes in nature the hydration of β-myrcene to linalool and the subsequent isomerization to geraniol. Enzymatic kinetic resolutions of truncated and elongated aromatic and aliphatic tertiary alcohols (C5-C15) that contain a specific signature motif demonstrate the broad substrate specificity of LinD. The three-dimensional structure of LinD from Castellaniella defragrans revealed a pentamer with active sites at the protomer interfaces. Furthermore, the structure of LinD in complex with the product geraniol provides initial mechanistic insights into this bifunctional enzyme. Site-directed mutagenesis confirmed active site amino acid residues essential for its dehydration and isomerization activity. These structural and mechanistic insights facilitate the development of hydrating catalysts, enriching the toolbox for novel bond-forming biocatalysis

Biokatalysatoren für die organische Synthese - die neue Generation

Nestl BM, Hammer S, Nebel BA, Hauer B. Biokatalysatoren für die organische Synthese - die neue Generation. Angewandte Chemie. 2014;126(12):3132-3158

New Generation of Biocatalysts for Organic Synthesis

Nestl BM, Hammer S, Nebel BA, Hauer B. New Generation of Biocatalysts for Organic Synthesis. Angewandte Chemie International Edition. 2014;53(12):3070-3095