554 Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells
About: This article is published in European Journal of Cancer.The article was published on 2014-11-01 and is currently open access. It has received 1 citation(s) till now. The article focuses on the topic(s): EHMT2 & Cancer epigenetics.
Summary (2 min read)
- Many cancers show aberrant silencing of gene expression and overexpression of histone methyltransferases, also known as Background.
- The histone methyltransferases (HKMT) EZH2 and EHMT2 maintain the repressive chromatin histone methylation marks H3K27me and H3K9me, respectively, which are associated with transcriptional silencing.
- Indeed, expression of certain genes is only induced upon dual inhibition.
- The compounds inhibit growth in a panel of breast cancer and lymphoma cell lines with low to sub-micromolar IC50s.
- The authors have demonstrated that dual inhibition of EZH2 and EHMT2 is more effective at eliciting biological responses of gene transcription and cancer cell growth inhibition compared to inhibition of single HKMTs, and they report the first dual EZH2-EHMT1/2 substrate competitive inhibitors that are functional in cells.
- EZH2 along with EED and SUZ12 are the indispensible core components of the Polycomb Repressive Complex (PRC2) responsible for maintenance of the repressive epigenetic mark H3K27me3: trimethylation of lysine 27 of histone 3 .
- This article International License (http://creativecommo reproduction in any medium, provided you link to the Creative Commons license, and Dedication waiver (http://creativecommons article, unless otherwise stated.
- Ated with gene amplification, has been well documented in a variety of cancers , .
- Combining this evidence, it would again suggest that specifically targeting either EZH2 or EHMT2 alone may not be sufficient to reverse epigenetic silencing of genes, but rather combined inhibition may be required.
- To this end, the authors have examined the effect of dual EZH2 and EHMT2 gene knockdown or enzyme inhibition in breast cancer cells.
- Each group has been compared to the untreated sample following normalisation to GAPDH.
- All hit compounds showed a dose-dependent increase of KRT17, FBXO32, as well as JMJD3 mRNA.
- Almost no enrichment was observed of this gene set in MDA-MB-231 cells after treatment with any of the compounds (HKMTI-1-005, GSK343 and UNC0638) (Fig. 4a), suggesting that EZH2 has cell-type-specific targets.
- Together, these data strongly support that the hit compound HKMT-I-005 reduces levels of H3K27me3 and H3K9me3 at concentrations of compound that are less or equivalent to the growth inhibition IC50 concentration for MDA- MB-231 (Table 2).
- It is widely accepted that the installation, maintenance and functional output of epigenetic modifications occur in concert via combinatorial sets of modifications.
- This suggests that the compounds are able to elicit a transcriptional response that is specific to a particular cell line, and thus, represent a means of tailoring the response to the targets that are specifically epigenetically repressed in the cancer cells to be treated.
- SPINK1 expression is increased upon treatment with HKMT-I-005, HKMT-I-011 and HKMT-I-022 at multiple doses and time points.
- Genome-wide expression analysis revealed that genes upregulated upon treatment with HKMTI-1-005 were more enriched for genes silenced by EZH2 than treatment with either the specific EHMT2 inhibitor UNC0638 or the specific EZH2 inhibitor GSK343.
- The hit compounds reported herein represent starting points for the further optimisation of dual EZH2/ EHMT2 inhibitors.
- Many cancers show aberrant silencing of gene expression and overexpression of histone methyltransferases, including EZH2 and EHMT1/2.
- The authors have shown that combined inhibition of EHMT1/2 and EZH2 increases growth inhibition in tumour cells over inhibition of only EHMT1/2 or EZH2 and results in re-expression of silenced genes.
- The authors report the first dual EZH2-EHMT1/2 substrate competitive inhibitors and show that they may have greater activity in tumour cells that overexpress wild type EZH2.
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Cites background from "554 Dual EZH2 and EHMT2 histone met..."
...Cotreatment with the Euchromatic Histone Lysine Methyltransferase 2 (EHMT2) inhibitor UNC0638 significantly inhibited the growth of breast cancer cells (Brown et al., 2014), suggesting that EZH2 inhibitors GSK343 could be a potential therapeutic option for cancer (Xiong et al., 2016)....
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Q1. What contributions have the authors mentioned in the paper "Dual ezh2 and ehmt2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells" ?
The authors report that gene expression and inhibition of triple negative breast cancer cell growth ( MDA-MB-231 ) are markedly increased when targeting both EZH2 and EHMT2, either by siRNA knockdown or pharmacological inhibition, rather than either enzyme independently. The authors sought to identify compounds which showed evidence of dual EZH2 and EHMT2 inhibition. The authors have demonstrated that dual inhibition of EZH2 and EHMT2 is more effective at eliciting biological responses of gene transcription and cancer cell growth inhibition compared to inhibition of single HKMTs, and they report the first dual EZH2-EHMT1/2 substrate competitive inhibitors that are functional in cells. Ac. uk Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK Department of Surgery and Cancer, Ovarian Cancer Action Research Centre, Imperial College London, Hammersmith Hospital Campus, London W12 ONN, UK Full list of author information is available at the end of the article © 2015 Curry et al. This article International License ( http: //creativecommo reproduction in any medium, provided you link to the Creative Commons license, and Dedication waiver ( http: //creativecommons article, unless otherwise stated. However, removal of the repressive mark H3K27me3 alone may not always be is distributed under the terms of the Creative Commons Attribution 4. 0 ns. org/licenses/by/4. 0/ ), which permits unrestricted use, distribution, and give appropriate credit to the original author ( s ) and the source, provide a indicate if changes were made. BIX-01294 ( see Fig. 2 ) was previously identified as an inhibitor of the HKMTs EHMT2 and EHMT1, and subsequent medicinal chemistry studies around the 2, 4-diamino-6, 7-dimethoxyquinazoline template of BIX01294 have yielded a number of follow-up EHMT2 inhibitors [ 20–25 ]. It has been suggested that this could provide cells with a mechanism to compensate in part for a loss of EZH2 [ 28 ]. To this end, the authors have examined the effect of dual EZH2 and EHMT2 gene knockdown or enzyme inhibition in breast cancer cells. Consistent with the requirement for removal of both repressive H3K9 and H3K27 methylation marks, the authors show that dual inhibition of EHMT2 and EZH2 pharmacologically or by SiRNA is necessary for reactivation of certain genes and induces greater inhibition of cell growth than targeting either HKMT alone in triple negative breast cancer MDA-MB-231 cells. Elimination of further repressive methylation marks by inhibition of additional HKMTs may be required to fully realise the epigenetic potential of HKMT inhibitors. The picture is further complicated by recent evidence that EHMT2 and EZH2 ( via the PRC2 complex ) interact physically and share targets for epigenetic silencing [ 29 ]. Combining this evidence, it would again suggest that specifically targeting either EZH2 or EHMT2 alone may not be sufficient to reverse epigenetic silencing of genes, but rather combined inhibition may be required. Further, the authors have identified proof-of-concept compounds which are dual ( substrate competitive ) EZH2-EHMT1/2 inhibitors.
Q2. What are the future works in "Dual ezh2 and ehmt2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells" ?
While this scaffold has been extensively pursued for selective EHMT1/2 inhibition, further studies are needed to confirm whether it is possible to simultaneously increase potency against both EZH2 and EHMT1/2 and whether it is possible to engineer EHMT1/2 activity out of this scaffold to identify a selective substrate competitive EZH2 inhibitor.