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Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors
TLDR
The structure of the histone deacetylase catalytic core is described, as revealed by the crystal structure of a homologue from the hyperthermophilic bacterium Aquifex aeolicus, and it is established that the residues that make up the active site and contact the inhibitors are conserved across the HDAC family. Expand
Histone deacetylases and cancer: causes and therapies
TLDR
Together, histone acetyltransferases and histone deacetylases determine the acetylation status of histones, and inhibitors of HDACs have been found to cause growth arrest, differentiation and/or apoptosis of many tumours cells by altering the transcription of a small number of genes. Expand
Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor.
TLDR
In vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model, providing compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL. Expand
MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.
TLDR
Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Expand
Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells.
TLDR
The working hypothesis is that inhibition of HDAC activity leads to the modulation of expression of a specific set of genes that, in turn, result in growth arrest, differentiation, and/or apoptotic cell death. Expand
Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation.
TLDR
The present findings indicate that the induction of p21(WAF1) by SAHA is regulated, at least in part, by the degree of acetylation of the gene-associated histones and that this induced increase in acetylations is gene selective. Expand
Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas
TLDR
The results imply that the malignant phenotype of disease requires the combined activities of a H3K27 monomethylating enzyme (PRC2 containing WT EZH2 or EZh1) together with the mutant PRC2s for augmented conversion of H3k27 to the trimethylated form. Expand
A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases.
TLDR
These studies show that the second-generation HPCs, unlike HMBA, are potent inhibitors of HDAC activity, and appear to induce differentiation by different pathways. Expand
A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells.
TLDR
The discovery of EPZ005687 is reported, a potent inhibitor of EZH2 that reduces H3K27 methylation in various lymphoma cells; this translates into apoptotic cell killing in heterozygous Tyr641 or Ala677 mutant cells, with minimal effects on the proliferation of wild-type cells. Expand
Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.
TLDR
The characterization of EPZ-5676 is described, a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity that demonstrates 37 000-fold selectivity over all other methyltransferases tested. Expand
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