BibTex format

author = {Curry, E and Green, I and Chapman-Rothe, N and Shamsaei, E and Kandil, S and Cherblanc, F and Payne, L and Bell, E and Ganesh, T and Srimongkolpithak, N and Caron, J and Li, F and Uren, AG and Snyder, JP and Vedadi, M and Fuchter, MJ and Brown, R},
doi = {10.1186/s13148-015-0118-9},
journal = {Clinical Epigenetics},
title = {Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells},
url = {},
volume = {7},
year = {2015}

RIS format (EndNote, RefMan)

AB - Background: Many cancers show aberrant silencing of gene expression andoverexpression of histone methyltransferases. The histone methyltransferases (HKMT)EZH2 and EHMT2 maintain the repressive chromatin histone marks H3K27 and H3K9methylation respectively, which are associated with transcriptional silencing. Althoughselective HKMT inhibitors reduce levels of individual repressive marks, removal ofH3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducingexpression of genes with multiple repressive marks.Results: We report that gene expression and inhibition of triple negative breast cancer cellgrowth (MDA-MB-231) are markedly increased when targeting both EZH2 and EHMT2,either by siRNA knockdown or pharmacological inhibition, rather than independently. Indeed,expression of certain genes is only induced upon dual inhibition. We sought to identifycompounds which showed evidence of dual EZH2 and EHMT2 inhibition. Using a cell-basedassay, based on the substrate-competitive EHMT2 inhibitor BIX01294, we have identifiedproof-of-concept compounds that induce re-expression of a subset of genes consistent withdual HKMT inhibition. Chromatin immunoprecipitation verified a decrease in silencing marksand an increase in permissive marks at the promoter and transcription start site of reexpressedgenes, while Western analysis showed reduction in global levels of H3K27me3and H3K9me3. The compounds inhibit growth in a panel of breast cancer and lymphoma celllines with low to sub-micromolar IC50s. Biochemically, the compounds are substratecompetitive inhibitors against both EZH2 and EHMT1/2.Conclusions: We have demonstrated that dual inhibition of EZH2 and EHMT2 is moreeffective at eliciting biological responses of gene transcription and cancer cell growthinhibition compared to inhibition of single HKMTs, and we report the first dual EZH2-EHMT1/2 substrate competitive inhibitors that are functional in cells.
AU - Curry,E
AU - Green,I
AU - Chapman-Rothe,N
AU - Shamsaei,E
AU - Kandil,S
AU - Cherblanc,F
AU - Payne,L
AU - Bell,E
AU - Ganesh,T
AU - Srimongkolpithak,N
AU - Caron,J
AU - Li,F
AU - Uren,AG
AU - Snyder,JP
AU - Vedadi,M
AU - Fuchter,MJ
AU - Brown,R
DO - 10.1186/s13148-015-0118-9
PY - 2015///
SN - 1868-7083
TI - Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells
T2 - Clinical Epigenetics
UR -
UR -
VL - 7
ER -