Dataset Information

Protein-Nanocaged Selenium Induces t(8;21) Leukemia Cell Differentiation via Epigenetic Regulation.

ABSTRACT: The success of arsenic in degrading PML-RARα oncoprotein illustrates the great anti-leukemia value of inorganics. Inspired by this, the therapeutic effect of inorganic selenium on t(8; 21) leukemia is studied, which has shown promising anti-cancer effects on solid tumors. A leukemia-targeting selenium nanomedicine is rationally built with bioengineered protein nanocage and is demonstrated to be an effective epigenetic drug for inducing the differentiation of t(8;21) leukemia. The selenium drug significantly induces the differentiation of t(8;21) leukemia cells into more mature myeloid cells. Mechanistic analysis shows that the selenium is metabolized into bioactive forms in cells, which drives the degradation of the AML1-ETO oncoprotein by inhibiting histone deacetylases activity, resulting in the regulation of AML1-ETO target genes. The regulation results in a significant increase in the expression levels of myeloid differentiation transcription factors PU.1 and C/EBPα, and a significant decrease in the expression level of C-KIT protein, a member of the type III receptor tyrosine kinase family. This study demonstrates that this protein-nanocaged selenium is a potential therapeutic drug against t(8;21) leukemia through epigenetic regulation.

SUBMITTER: Fang L

PROVIDER: S-EPMC10724402 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Protein-Nanocaged Selenium Induces t(8;21) Leukemia Cell Differentiation via Epigenetic Regulation.

Fang Long L Zhang Ruofei R Shi Lin L Xie Jiaying J Ma Long L Yang Yili Y Yan Xiyun X Fan Kelong K

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20231027 35

The success of arsenic in degrading PML-RARα oncoprotein illustrates the great anti-leukemia value of inorganics. Inspired by this, the therapeutic effect of inorganic selenium on t(8; 21) leukemia is studied, which has shown promising anti-cancer effects on solid tumors. A leukemia-targeting selenium nanomedicine is rationally built with bioengineered protein nanocage and is demonstrated to be an effective epigenetic drug for inducing the differentiation of t(8;21) leukemia. The selenium drug s ...[more]

PMID: 37888866

Similar Datasets

Project description:A cute myeloid leukemia is a malignant disease of immature myeloid cells. Despite significant therapeutic effects of differentiation-inducing agents in some acute myeloid leukemia subtypes, the disease remains incurable in a large fraction of patients. Here we show that SK053, a thioredoxin inhibitor, induces differentiation and cell death of acute myeloid leukemia cells. Considering that thioredoxin knock-down with short hairpin RNA failed to exert antiproliferative effects in one of the acute myeloid leukemia cell lines, we used a biotin affinity probe-labeling approach to identify potential molecular targets for the effects of SK053. Mass spectrometry of proteins precipitated from acute myeloid leukemia cells incubated with biotinylated SK053 used as a bait revealed protein disulfide isomerase as a potential binding partner for the compound. Biochemical, enzymatic and functional assays using fluorescence lifetime imaging confirmed that SK053 binds to and inhibits the activity of protein disulfide isomerase. Protein disulfide isomerase knockdown with short hairpin RNA was associated with inhibition of cell growth, increased CCAAT enhancer-binding protein α levels, and induction of differentiation of HL-60 cells. Molecular dynamics simulation followed by the covalent docking indicated that SK053 binds to the fourth thioredoxin-like domain of protein disulfide isomerase. Differentiation of myeloid precursor cells requires the activity of CCAAT enhancer-binding protein α, the function of which is impaired in acute myeloid leukemia cells through various mechanisms, including translational block by protein disulfide isomerase. SK053 increased the levels of CCAAT enhancer-binding protein α and upregulated mRNA levels for differentiation-associated genes. Finally, SK053 decreased the survival of blasts and increased the percentage of cells expressing the maturation-associated CD11b marker in primary cells isolated from bone marrow or peripheral blood of patients with acute myeloid leukemia. Collectively, these results provide a proof-of-concept that protein disulfide isomerase inhibition has potential as a therapeutic strategy for the treatment of acute myeloid leukemia and for the development of small-molecule inhibitors of protein disulfide isomerase.

Dataset Information

Protein-Nanocaged Selenium Induces t(8;21) Leukemia Cell Differentiation via Epigenetic Regulation.

Publications

Protein-Nanocaged Selenium Induces t(8;21) Leukemia Cell Differentiation via Epigenetic Regulation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets