DZNep Is a Global Histone Methylation Inhibitor that Reactivates Developmental Genes Not Silenced by DNA Methylation

By T. Miranda, C. Cortez, C. Yoo, G. Liang, Masanobu Abe, T. Kelly, V. Marquez, Peter A. Jones. Molecular Cancer Therapeutics, 2009

605 citations recorded by the source corpus.

DNA methylation, histone modifications, and nucleosomal occupancy collaborate to cause silencing of tumor-related genes in cancer. The development of drugs that target these processes is therefore important for cancer therapy. Inhibitors of DNA methylation and histone deacetylation have been approved by the Food and Drug Administration for treatment of hematologic malignancies. However, drugs that target other mechanisms still need to be developed. Recently, 3-deazaneplanocin A (DZNep) was reported to selectively inhibit trimethylation of lysine 27 on histone H3 (H3K27me3) and lysine 20 on histone H4 (H4K20me3) as well as reactivate silenced genes in cancer cells. This finding opens the door to the pharmacologic inhibition of histone methylation. We therefore wanted to further study the mechanism of action of DZNep in cancer cells. Western blot analysis shows that DZNep globally inhibits histone methylation and is not selective. Two other drugs, sinefungin and adenosine dialdehyde, have similar effects as DZNep on H3K27me3. Intriguingly, chromatin immunoprecipitation of various histone modifications and microarray analysis show that DZNep acts through a different pathway than 5-aza-2′-deoxycytidine, a DNA methyltransferase inhibitor. These observations give us interesting insight into how chromatin structure affects gene expression. We also determined the kinetics of gene activation to understand if the induced changes were somatically heritable. We found that upon removal of DZNep, gene expression is reduced to its original state. This suggests that there is a homeostatic mechanism that returns the histone modifications to their “ground state” after DZNep treatment. Our data show the strong need for further development of histone methylation inhibitors. [Mol Cancer Ther 2009;8(6):1579–88]

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ce0da1ab9299f0aea0d1560035fe9649bc66711b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

Epigenetic Modifications as Therapeutic Targets (2010, background): “This demonstration that DZNep lacks specificity and acts more as a global histone methylation inhibitor underscores the need for further development of histone methylation inhibitor”
Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. (2011, background): “2 M biotinylated peptide substrate (ie, peptide mimicking the H3 tail, H3(21-44)), which has been unmethylated (H3K27me0, open bar or me0), monomethylated (H3K27me1, gray bar or me1) or dimethylated (H3K27me2, black bar or me2) at Lys-27.”
Cooperation between Constitutive and Inducible Chemokines Enables T-cell Engraftment and Immune Attack in Solid Tumors (2019, background): “Conversely, the global histone methylation inhibitor 3Deazaneplanocin A (DZNep), which induces EZH2 protein depletion (Miranda et al., 2009), upregulated CCL5 in only 1 out of 4 cell lines tested.”