Targeting of cancer stem cells by inhibitors of DNA and histone methylation

Momparler, Richard L.; Côté, Sylvie

doi:10.1517/13543784.2015.1051220

Cited by 43 publications

(30 citation statements)

References 89 publications

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“…25 Through H3K27me3, EZH2 suppresses differentiation of mesenchymal stem cells and potential cancer stem cells. 26 Point mutations that increase the catalytic activity of EZH2 promote cell transformation in subsets of B-cell neoplasms, thus making EZH2 a compelling target in this genetically defined patient population. 27 EZH2 inhibitors were shown to have strong antitumor effects against human B-cell lymphoma xenograft models.…”

Section: Discussionmentioning

confidence: 99%

Initial testing (stage 1) of tazemetostat (EPZ‐6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program

Kurmasheva

Sammons

Favours

et al. 2016

Pediatric Blood & Cancer

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Background Tazemetostat (EPZ-6438) is a selective inhibitor of the histone methyltransferase EZH2, currently in clinical development for non-Hodgkin lymphoma and genetically defined tumors. Procedures Tazemetostat was tested against the PPTP solid tumor xenografts using a dose of 400 mg/kg administered twice-daily by oral gavage for 28 days. H3K27me3:H3 ratios were determined in control and treated tumors. Results Tazemetostat induced significant differences in event free survival (EFS) distribution compared to control in 9 of 30 (30%) of the xenografts studied. Significant differences in EFS distribution were observed in 5 of 7 (71%) rhabdoid tumor xenograft lines compared to 4 of 23 (17%) non-rhabdoid xenograft lines [chi square (χ2) test p=0.006]. Tazemetostat induced tumor growth inhibition meeting criteria for intermediate and high EFS treated to control (T/C) activity in 2 of 25 (8%) and 1 of 25 (4%) xenografts, respectively. Intermediate and high activity for the EFS T/C metric was observed exclusively among rhabdoid tumor xenografts (3 of 5 rhabdoid tumor versus 0 of 22 non-rhabdoid tumors (χ2 test p<0.001). One rhabdoid tumor xenograft (G401) showed stable disease. For one rhabdoid tumor (G401), delayed tumor regression to tazemetostat was noted following 1 week of tumor growth. Tazemetostat induced significant reduction of H3K27me3 levels in the majority of tumors compared to controls. Conclusions Tazemetostat demonstrated significant antitumor activity in rhabdoid tumor models, but showed no consistent activity against any other histology. Tazemetostat reduced H3K27me3 levels irrespective of tumor response. Further preclinical testing to evaluate tazemetostat in combination with other anticancer agents is warranted.

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Section: Discussionmentioning

confidence: 99%

Initial testing (stage 1) of tazemetostat (EPZ‐6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program

Kurmasheva

Sammons

Favours

et al. 2016

Pediatric Blood & Cancer

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“…The upstream regulatory mechanisms of HOTAIR expression in OA also need to be determined, which may involve interactions with other lncRNAs (54) or mechanoresponsive pathways (55). Furthermore, histone methylation is known to be affected by inhibitors of DNA methylation, such as 5-Aza-2'-deoxycytidine which is used as an anti-cancer drug (56,57), and it would be interesting to investigate the effects of applying such compounds on HOTAIR signalling in OA. These additional ndings building on the results of this study will con rm our proposed mechanism, and potentially improve the accuracy of predictive models for the pathogenesis of cartilage damage in OA (58).…”

Section: Discussionmentioning

confidence: 99%

A long non-coding RNA, HOTAIR, promotes cartilage degradation in osteoarthritis by inhibiting WIF-1 expression and activating Wnt pathway

Yang

Xing

Wang

et al. 2020

Preprint

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Abstract Background: Long noncoding RNAs (lncRNAs) are recently found to be critical regulators of the epigenome. However, our knowledge of their role in osteoarthritis (OA) development is limited. This study investigates the mechanism by which HOTAIR, a key lncRNA with elevated expression in OA, affects OA disease progression.Results: HOTAIR expression was greatly elevated in osteoarthritic compared to normal chondrocytes. Silencing and over-expression of HOTAIR in SW1353 cells respectively reduced and increased the expression of genes associated with cartilage degradation in OA. Investigation of molecular pathways revealed that HOTAIR acted directly on Wnt inhibitory factor 1 (WIF-1) by increasing histone H3K27 trimethylation in the WIF-1 promoter, leading to WIF-1 repression that favours activation of the Wnt/β-catenin pathway.Conclusions: Activation of Wnt/β-catenin signalling by HOTAIR through WIF-1 repression in osteoarthritic chondrocytes increases catabolic gene expression and promotes cartilage degradation. This is the first study to demonstrate a direct link between HOTAIR, WIF-1 and OA progression, which may be useful for future investigations into disease biomarkers or therapeutic targets.

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“…Recently, preclinical studies have shown that ( 1 ) in combination with 3-deazaneplanocin-A (DZNep) ( 8 ) produce a synergistic reactivation of CDKN1A (Cyclin-dependent kinase inhibitor 1A), CDKN1B and FBXO32 (F-Box Protein 32) genes [32,33]. In fact, ( 8 ) is an inhibitor of S -adenosyl-L-homocysteine (SAH) hydrolase, an enzyme involved in the degradation of SAH (or AdoHcy), the product of the methylation reaction and a natural inhibitor of HMTs and other enzymes.…”

Section: Inhibition Of Dna Methylationmentioning

confidence: 99%

“…As evoked above, the combination of DNMTi 1 and the SAH hydrolase inhibitor ( 8 ) represents this emerging approach [33]. Furthermore, keeping in mind that SAM is the cofactor of both DNMT and HMTs, dual inhibitors, i.e., agents with a double effect, might also represent an interesting anticancer approach [84].…”

Section: Inhibition Of Dna Methylation: Other Approachesmentioning

confidence: 99%

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

et al. 2017

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Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action.

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Targeting of cancer stem cells by inhibitors of DNA and histone methylation

Cited by 43 publications

References 89 publications

Initial testing (stage 1) of tazemetostat (EPZ‐6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program

Initial testing (stage 1) of tazemetostat (EPZ‐6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program

A long non-coding RNA, HOTAIR, promotes cartilage degradation in osteoarthritis by inhibiting WIF-1 expression and activating Wnt pathway

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

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