Astemizole Arrests the Proliferation of Cancer Cells by Disrupting the EZH2-EED Interaction of Polycomb Repressive Complex 2

Kong, Xiangqian; Chen, Limin; Jiao, Libin; Jiang, Xiangrui; Lian, Fulin; Lu, Junyan; Zhu, Kongkai; Du, Daohai; Liu, Ying; Ding, Hong; Zhang, Naixia; Shen, Jingshan; Zheng, Mingyue; Chen, Kaixian; Liu, Xin; Jiang, Hualiang; Luo, Cheng

doi:10.1021/jm501230c

Cited by 97 publications

(76 citation statements)

References 75 publications

(122 reference statements)

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“…Strikingly, in contrast to the anticipated enhancement of viral gene expression, each compound suppressed viral IE gene transcription in a dose-dependent manner. Similarly, treatment with astemizole, a compound that interferes with the association of EZH2/1 with the chromatin binding subunit of the PRC2 complex (EED, embryonic ectoderm development) (24), also suppressed viral IE gene expression ( Fig. 1A and E to F).…”

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confidence: 87%

“…More recently, inhibitors of the histone H3K27 methyltransferases EZH2 and EZH1 (EZH2/1) have been developed as potential therapeutics for treating cancers with EZH2 gain-of-function mutations (22)(23)(24)(25)(26)(27)(28)(29)(30). As components of Polycomb repressive complex 2 (PRC2), EZH2/1 mediate gene repression primarily through propagation of H3K27me3, which results in domains of nucleosomal compaction (31)(32)(33).…”

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confidence: 99%

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Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens

Arbuckle

Gardina

Gordon

et al. 2017

mBio

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Epigenetic regulation is based on a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression, cell fate, and development. Thus, epigenetic modulators represent novel therapeutic targets used to treat a range of diseases, including malignancies. Infectious pathogens such as herpesviruses are also regulated by cellular epigenetic machinery, and epigenetic therapeutics represent a novel approach used to control infection, persistence, and the resulting recurrent disease. The histone H3K27 methyltransferases EZH2 and EZH1 (EZH2/1) are epigenetic repressors that suppress gene transcription via propagation of repressive H3K27me3-enriched chromatin domains. However, while EZH2/1 are implicated in the repression of herpesviral gene expression, inhibitors of these enzymes suppressed primary herpes simplex virus (HSV) infection in vitro and in vivo. Furthermore, these compounds blocked lytic viral replication following induction of HSV reactivation in latently infected sensory ganglia. Suppression correlated with the induction of multiple inflammatory, stress, and antipathogen pathways, as well as enhanced recruitment of immune cells to in vivo infection sites. Importantly, EZH2/1 inhibitors induced a cellular antiviral state that also suppressed infection with DNA (human cytomegalovirus, adenovirus) and RNA (Zika virus) viruses. Thus, EZH2/1 inhibitors have considerable potential as general antivirals through the activation of cellular antiviral and immune responses.IMPORTANCE A significant proportion of the world's population is infected with herpes simplex virus. Primary infection and subsequent recurrent reactivation can result in diseases ranging from mild lesions to severe ocular or neurological damage. Herpesviruses are subject to epigenetic regulation that modulates viral gene expression, lytic replication, and latency-reactivation cycles. Thus, epigenetic pharmaceuticals have the potential to alter the course of infection and disease. Here, while the histone methyltransferases EZH2/1 are implicated in the suppression of herpesviruses, inhibitors of these repressors unexpectedly suppress viral infection in vitro and in vivo by induction of key components of cellular innate defense pathways. These inhibitors suppress infection by multiple viral pathogens, indicating their potential as broad-spectrum antivirals.KEYWORDS antiviral, chromatin, epigenetics, herpesvirus, immune mechanisms, innate immunity, Zika virus F ollowing primary infection with herpes simplex virus (HSV), the virus establishes lifelong latency in sensory neurons. However, multiple biological or stress stimuli can induce reactivation of latent genomes and recurrent disease. Ocular HSV infections remain the leading virus-mediated cause of stromal keratitis and corneal scarring, while

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confidence: 87%

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confidence: 99%

Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens

Arbuckle

Gardina

Gordon

et al. 2017

mBio

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“…Stabilized alpha-helix of EZH2 (SAH-EZH2) peptides disrupt the EZH2/EED interaction and decrease the EZH2 levels leading to decreased methyltransferase activity leading to growth arrest and differentiation of MLL-AF9 leukemic cells [109]. Similarly, Astemizole is a small molecule inhibitor of EZH2/EED interaction which destabilizes PRC2 complex decreasing the proliferation of lymphoma cells [110]. Finally, CPI-1205 selectively inhibits the interaction of EZH2 with PRC2 complex and is currently evaluated in a phase 1 clinical trial in patients with B-cell lymphomas (NCT02395601).…”

Section: Targeting Of Ezh2 For Cancer Therapymentioning

confidence: 99%

Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2

et al. 2016

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Polycomb group proteins regulate chromatin structure and have an important regulatory role on gene expression in various cell types. Two polycomb group complexes (Polycomb repressive complex 1 (PRC1) and 2 (PRC2)) have been identified in mammalian cells. Both PRC1 and PRC2 compact chromatin, and also catalyze histone modifications. PRC1 mediates monoubiquitination of histone H2A, whereas PRC2 catalyzes methylation of histone H3 on lysine 27. These alterations of histones can lead to altered gene expression patterns by regulating chromatin structure. Numerous studies have highlighted the role of the PRC2 catalytic component enhancer of zeste homolog 2 (EZH2) in neoplastic development and progression, and EZH2 mutations have been identified in various malignancies. Through modulating the expression of critical genes, EZH2 is actively involved in fundamental cellular processes such as cell cycle progression, cell proliferation, differentiation and apoptosis. In addition to cancer cells, EZH2 also has a decisive role in the differentiation and function of T effector and T regulatory cells. In this review we summarize the recent progress regarding the role of EZH2 in human malignancies, highlight the molecular mechanisms by which EZH2 aberrations promote the pathogenesis of cancer, and discuss the anti-tumor effects of EZH2 targeting via activating direct anti-cancer mechanisms and anti-tumor immunity.

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“…Recently, it has been identified that Astemizole, a drug previously used in the treatment of seasonal allergic rhinitis, is an inhibitor of the EED/EZH2 protein-protein interaction. Astemizole competes with EZH2 for the binding with EED, destabilizing PRC2 complex and inducing cell cycle arrest in leukemia cells [112] . Interestingly, the combination treatment of SAH-EZH2 or astemizole and various SAM analogues produced a significant synergistic effect on lymphoma cells [111,112] , indicating that the suppression of catalytic activity and the disruption of PRC2 complex could influence different pathways and a combinatorial drug therapy can be a more effective therapeutic strategy.…”

Section: Inhibition Of the Interaction Between Ezh2 With Other Prc2 Smentioning

confidence: 99%

Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

Marchesi

Bagella

2016

WJCO

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Polycomb group proteins represent a global silencing system involved in development regulation. In specific, they regulate the transition from proliferation to differentiation, contributing to stem-cell maintenance and inhibiting an inappropriate activation of differentiation programs. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2, which induces transcriptional inhibition through the tri-methylation of histone H3, an epigenetic change associated with gene silencing. EZH2 expression is high in precursor cells while its level decreases in differentiated cells. EZH2 is upregulated in various cancers with high levels associated with metastatic cancer and poor prognosis. Indeed, aberrant expression of EZH2 causes the inhibition of several tumor suppressors and differentiation genes, resulting in an uncontrolled proliferation and tumor formation. This editorial explores the role of Polycomb repressive complex 2 in cancer, focusing in particular on EZH2. The canonical function of EZH2 in gene silencing, the non-canonical activities as the methylation of other proteins and the role in gene transcriptional activation, were summarized. Moreover, mutations of EZH2, responsible for an increased methyltransferase activity in cancer, were recapitulated. Finally, various drugs able to inhibit EZH2 with different mechanism were described, specifically underscoring the effects in several cancers, in order to clarify the role of EZH2 and understand if EZH2 blockade could be a new strategy for developing specific therapies or a way to increase sensitivity of cancer cells to standard therapies.

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Astemizole Arrests the Proliferation of Cancer Cells by Disrupting the EZH2-EED Interaction of Polycomb Repressive Complex 2

Cited by 97 publications

References 75 publications

Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens

Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens

Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2

Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

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