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

Molecular basis of the NO trans influence in quaternary T-state human hemoglobin: A computational study.

NO binding to the T-state of human hemoglobin (HbA) induces the cleavage of the proximal His bonds to the heme iron in the α-chains, whereas it leaves the β-hemes hexacoordinated. The structure of the nitrosylated T-state of the W37Eβ mutant (W37E) shows that the Fe-His87α bond remains intact. Exactly how mutation affects NO binding and why tension is apparent only in HbA α-heme remains to be elucidated. By means of density functional theory electronic structure calculations and classical molecular dynamics simulations we provide an explanation for the poorly understood NO binding properties of HbA and its W37E mutant. The data suggest an interplay between electronic effects, tertiary structure and hydration site modifications in determining the tension in the NO-ligated T-state HbA α-chain

Peculiar features in the crystal structure of the adduct formed between cis-PtI2(NH3)2 and hen egg white lysozyme.

The reactivity of cis-diamminediiodidoplatinum(II), cis-PtI2(NH3)2, the iodo analogue of cisplatin, with hen egg white lysozyme (HEWL) was investigated by electrospray ionization mass spectrometry and X-ray crystallography. Interestingly, the study compound forms a stable 1:1 protein adduct for which the crystal structure was solved at 1.99 Å resolution. In this adduct, the Pt(II) center, upon release of one ammonia ligand, selectively coordinates to the imidazole of His15. Both iodide ligands remain bound to platinum, with this being a highly peculiar and unexpected feature. Notably, two equivalent modes of Pt(II) binding are possible that differ only in the location of I atoms with respect to ND1 of His15. The structure of the adduct was compared with that of HEWL-cisplatin, previously described; differences are stressed and their important mechanistic implications discussed

Synthesis and crystal structure of low ferrialuminosilicate sanidine

Iron-containing potassium feldspar crystals are prepared using the hydrothermal synthesis in an alkaline medium at temperatures ranging from 500 to 526°C. The crystal structure of the synthetic potassium feldspar is refined [Ital Structures diffractometer, MoKalpha radiation, 1327 unique reflections with F > 4sigma(F), anisotropic approximation, R(F) = 0.044]. It is established that, under the given preparation conditions, the synthesis leads to the formation of the monoclinic modification with the following unit-cell parameters: a 8.655(7) Å, b = 13.101(9) Å, c = 7.250(g) Å, beta = 116.02(2)°, space group C2/m, and Z = 4. The cation distribution over crystallographically inequivalent tetrahedral positions T(1) and T(2) is determined and justified using X-ray diffraction data. According to this distribution, the iron-containing potassium feldspar is assigned to the low ferrialuminosilicate sanidine. The proposed structural formula K A=0.99 (Si1.2Fe0.5Al0.3) T(1)=2 (Si1.81Al0.19) T(2)=2 O8 agrees well with the data of the electron microprobe analysis. It is revealed that iron occupies the T(1) position and manifests itself as a majority rather than minority impurity element with respect to aluminum