1. The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML.
- Author
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Zhou J, Bi C, Cheong LL, Mahara S, Liu SC, Tay KG, Koh TL, Yu Q, and Chng WJ
- Subjects
- Adenosine pharmacology, Animals, Apoptosis, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Blotting, Western, Carrier Proteins antagonists & inhibitors, Carrier Proteins genetics, Cell Proliferation, Chromatin Immunoprecipitation, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins genetics, Enhancer of Zeste Homolog 2 Protein, Epigenomics, Female, Gene Expression Profiling, Gene Silencing, Histone Methyltransferases, Histone-Lysine N-Methyltransferase antagonists & inhibitors, Humans, Leukemia, Myeloid, Acute genetics, Mice, Mice, Inbred NOD, Mice, SCID, Oligonucleotide Array Sequence Analysis, Polycomb Repressive Complex 2, Polycomb-Group Proteins, RNA, Messenger genetics, RNA, Small Interfering genetics, Repressor Proteins antagonists & inhibitors, Repressor Proteins genetics, Repressor Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors antagonists & inhibitors, Transcription Factors genetics, Tumor Cells, Cultured, Adenosine analogs & derivatives, Carrier Proteins metabolism, DNA-Binding Proteins metabolism, Enzyme Inhibitors pharmacology, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute metabolism, Reactive Oxygen Species metabolism, Transcription Factors metabolism
- Abstract
Recent studies have shown that 3-Deazaneplanocin A (DZNep), a histone methyltransferase inhibitor, disrupts polycomb-repressive complex 2 (PRC2), and preferentially induces apoptosis in cancer cells, including acute myeloid leukemia (AML). However, the underlying molecular mechanisms are not well understood. The present study demonstrates that DZNep induces robust apoptosis in AML cell lines, primary cells, and targets CD34(+)CD38(-) leukemia stem cell (LSC)-enriched subpopulations. Using RNA interference (RNAi), gene expression profiling, and ChIP, we identified that TXNIP, a major redox control molecule, plays a crucial role in DZNep-induced apoptosis. We show that disruption of PRC2, either by DZNep treatment or EZH2 knockdown, reactivates TXNIP, inhibits thioredoxin activity, and increases reactive oxygen species (ROS), leading to apoptosis. Furthermore, we show that TXNIP is down-regulated in AML and is a direct target of PRC2-mediated gene silencing. Consistent with the ROS accumulation on DZNep treatment, we also see a signature of endoplasmic reticulum (ER) stress-regulated genes, commonly associated with cell survival, down-regulated by DZNep. Taken together, we uncover a novel molecular mechanism of DZNep-mediated apoptosis and propose that EZH2 may be a potential new target for epigenetic treatment in AML.
- Published
- 2011
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