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.