Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia

Xu, Bowen; On, Doan M.; Ma, Anqi; Parton, Trevor; Konze, Kyle D.; Pattenden, Samantha G.; Allison, David F.; Cai, Ling; Rockowitz, Shira; Liu, Shichong; Liu, Ying; Li, Fengling; Vedadi, Masoud; Frye, Stephen V.; García, Benjamin A.; Zheng, Deyou; Jin, Jian; Wang, Gang Greg

doi:10.1182/blood-2014-06-581082

Cited by 191 publications

(205 citation statements)

References 57 publications

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“…Therefore, it is not possible to conclude that the diminution of memory by compound is a result of changing H3K27me3 levels as reduced transcription could also be at play. We then asked if globally reducing the levels of H3K27me3 with the Ezh2 inhibitor UNC1999 (34) in the absence of a C/EBP␣ pulse could impart the same transcriptional memory phenomenon. Following the experimental design depicted in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The level of H3K27me3 at enhancers is generally low, making it difficult to draw conclusions based exclusively on ChIP studies. Therefore, to substantiate the importance of H3K27 demethylation on memory establishment and retention, we used small-molecule inhibitors that impair the enzymatic activity of the H3K27me3 demethylases and methylases, namely, Jmjd3/Utx (inhibited by glycogen synthase kinase [GSK]-J1/J4) (33) and Ezh1/2 (inhibited by UNC1999) (34). If H3K27 demethylation and retention contribute to memory, then blocking demethylation during the pulse should reduce the memory effect.…”

Section: Resultsmentioning

confidence: 99%

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A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory

Iberg-Badeaux

Collombet

Beaugerie

et al. 2017

Molecular and Cellular Biology

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Short-term and long-term transcriptional memory is the phenomenon whereby the kinetics or magnitude of gene induction is enhanced following a prior induction period. Short-term memory persists within one cell generation or in postmitotic cells, while long-term memory can survive multiple rounds of cell division. We have developed a tissue culture model to study the epigenetic basis for longterm transcriptional memory (LTTM) and subsequently used this model to better understand the epigenetic mechanisms that enable heritable memory of temporary stimuli. We find that a pulse of transcription factor CCAAT/enhancer-binding protein alpha (C/EBP␣) induces LTTM on a subset of target genes that survives nine cell divisions. The chromatin landscape at genes that acquire LTTM is more repressed than at those genes that do not exhibit memory, akin to a latent state. We show through chromatin immunoprecipitation (ChIP) and chemical inhibitor studies that RNA polymerase II (Pol II) elongation is important for establishing memory in this model but that Pol II itself is not retained as part of the memory mechanism. More generally, our work reveals that a transcription factor involved in lineage specification can induce LTTM and that failure to rerepress chromatin is one epigenetic mechanism underlying transcriptional memory.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory

Iberg-Badeaux

Collombet

Beaugerie

et al. 2017

Molecular and Cellular Biology

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“…Consistently, EZH1 mRNA (Figure 4(B)) and protein (Figure 4(C)) levels were suppressed by miR-17-5p mimic but increased by miR-17-5p inhibitor. As previous studies have shown that Cdkn2a is an important target of EZH1 and EZH1 represses Cdkn2a expression [27,28], we also measured the Cdkn2a levels. The results showed that miR-17-5p mimic increased Cdkn2a level while miR-17-5p inhibitor reduced Cdkn2a level (Figure 4(C)).…”

Section: Ezh1 Is a Target Of Mir-17-5pmentioning

confidence: 99%

miR-17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells

Zhang

Lin

Wang

et al. 2016

Journal of Drug Targeting

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Non-small cell lung cancer (NSCLC) is the major cause of lung cancer-related deaths. Erlotinib is an effective drug for NSCLC patients, but its effect in advanced NSCLC is compromised because of the drug resistance. The mechanism of erlotinib resistance in NSCLC is largely unknown. In the current study, we found that erlotinib treatment down-regulated miR-17-5p level in A549 cells and miR-17-5p was lower in acquired erlotinib-resistant A549 cells (A549-ER) compared with erlotinib-sensitive A549 cells. Consistently, miR-17-5p was down-regulated in the tumor tissues and the plasma of erlotinib-resistant NSCLC patients in comparison to those who are sensitive to erlotinib. Moreover, miR-17-5p mimic increased the sensitivity of A549 and A549-ER to erlotinib. In contrast, miR-17-5p inhibitor decreased the cell death of A549 and A549-ER induced by erlotinib. In addition, we also demonstrated that miR-17-5p could inhibit the mRNA and protein levels of enhancer of zeste homolog (EZH) 1, a member of the EZH family that contributes to drug resistance in several types of cancer. The luciferase assay of 3 0 -untranslated region (UTR) demonstrates that EZH1 is a direct target of miR-17-5p and EZH1 RNAi recapitulates the effect of miR-17-5p overexpression on erlotinib resistance. Further, mutation in seed sequence of miR-17-5p could totally abolish the sensitization of A549-ER to erlotinib induced by miR-17-5p overexpression. Our results indicate that miR-17-5p down-regulation contributes to erlotinib resistance of NSCLC by modulating its target genes such as EZH1 and plasma miR-17-5p might be a potential biomarker of erlotinib response in NSCLC patients. ARTICLE HISTORY

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“…Recently, it was suggested that EZH2 inhibitors are also effective in the treatment of AML (41). Thus, the potential for KDM1A inhibitors to work in combination with EZH2 inhibitors was investigated.…”

Section: Kdm1a Inhibitors Combine With Other Agents For the Treatmentmentioning

confidence: 99%

Pharmacological Inhibition of the Histone Lysine Demethylase KDM1A Suppresses the Growth of Multiple Acute Myeloid Leukemia Subtypes

et al. 2016

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Lysine-specific demethylase 1 (KDM1A) is a transcriptional coregulator that can function in both the activation and repression of gene expression, depending upon context. KDM1A plays an important role in hematopoiesis and was identified as a dependency factor in leukemia stem cell populations. Therefore, we investigated the consequences of inhibiting KDM1A in a panel of cell lines representing all acute myelogenous leukemia (AML) subtypes using selective, reversible and irreversible KDM1A smallmolecule inhibitors. Cell models of AML, CML, and T-ALL were potently affected by KDM1A inhibition, and cells bearing RUNX1-RUNX1T1 (AML1-ETO) translocations were especially among the most sensitive. RNAi-mediated silencing of KDM1A also effectively suppressed growth of RUNX1-RUNX1T1-containing cell lines. Furthermore, pharmacologic inhibition of KDM1A resulted in complete abrogation of tumor growth in an AML xenograft model harboring RUNX1-RUNX1T1 translocations. We unexpectedly found that KDM1A-targeting compounds not only inhibited the catalytic activity of the enzyme, but evicted KDM1A from target genes. Accordingly, compound-mediated KDM1A eviction was associated with elevated levels of local histone H3 lysine 4 dimethylation, and increased target gene expression, which was further accompanied by cellular differentiation and induction of cell death. Finally, our finding that KDM1A inhibitors effectively synergize with multiple conventional as well as candidate anti-AML agents affords a framework for potential future clinical application. Cancer Res; 76(7); 1975-88. Ó2016 AACR.

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Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia

Abstract: Key Points We characterize active vs inactive analog compounds suitable for inhibition of both PRC2-EZH2 and PRC2-EZH1 ex vivo and in vivo. This study is the first to show oral delivery of an EZH2 and EZH1 dual inhibitor as promising therapeutics for MLL-rearranged leukemia.

Cited by 191 publications

References 57 publications

A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory

A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory

miR-17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells

Pharmacological Inhibition of the Histone Lysine Demethylase KDM1A Suppresses the Growth of Multiple Acute Myeloid Leukemia Subtypes

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