Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy

Morera, Ludovica; Lübbert, Michael; Jung, Manfred

doi:10.1186/s13148-016-0223-4

Cited by 355 publications

(235 citation statements)

References 189 publications

(194 reference statements)

Supporting

Mentioning

233

Contrasting

Unclassified

Order By: Relevance

“…Recently, inhibitors of the histone H3K27 methyltransferases EZH2/1 have been developed on the basis of the potential to treat some diffuse large B-cell, follicular, and non-Hodgkin's lymphomas (23,(55)(56)(57). Importantly, pharmacological inhibition of EZH2/1 has shown promising results in tumor regression in cancer cell lines, mouse tumor xenograft models, and human phase I trials (7,23,(25)(26)(27)(28)(29)(30)58).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

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

View full text Add to dashboard Cite

show abstract

“…In line with these findings, pharmacologic inhibition of EZH2 decreased proliferation, tumorigenicity, and invasion while inducing apoptosis in vitro and in vivo [8,17]. Accordingly, the efficacy of EZH2 inhibitors has been well documented in animal models and come of them are currently undergoing highly anticipated clinical testing [18,19].…”

Section: Introductionmentioning

confidence: 79%

Elevated expression of a pharmacologic Polycomb signature predicts poor prognosis in gastric and breast cancer

2017

View full text Add to dashboard Cite

Aims: Polycomb Group (PcG) complexes are epigenetic repressors that silence tumor suppressive genes. Studies demonstrated that pharmacologic inhibition of PcG complexes with 3-deazaneplanocin A (DZNeP) induces cancer cell death by re-expressing silenced genes. Here, we evaluate the prognostic significance of DZNeP target genes in gastric and breast cancer.Patients & Methods/Materials: The prognostic impact of a DZNeP-regulated gene signature was investigated using the KM Plotter and cBio Portal resources containing microarray data from tumor tissue.Results: We report that elevated expression of DZNeP targets is associated with poor clinical outcome in gastric and breast cancer. In gastric cancer, elevated expression of DZNeP signature is inversely correlated with decreased overall survival. In breast cancer, DZNeP signature predicted poor prognosis in HER2+ tumors but not in HER2-neoplasms.Conclusions: These findings demonstrate that DZNeP target genes are not predictive of better but rather of poor clinical outcome in gastric and breast cancer.

show abstract

“…They can be removed by histone lysine demethylases (KDMs), such as LSD-1 and -2, or JmJDdomain-containing histone demethylases. 13,14 LSD1 demethylates mono-and di-methylated lysines 4 and 9 of histone H3. It is frequently overexpressed in NSCLC and promotes proliferation and invasion.…”

Section: Histone Modifications: Enzymes and Their Inhibitorsmentioning

confidence: 99%

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

et al. 2016

Self Cite

View full text Add to dashboard Cite

Non-small cell lung cancer (NSCLC) still constitutes the most common cancer-related cause of death worldwide. All efforts to introduce suitable treatment options using chemotherapeutics or targeted therapies have, up to this point, failed to exhibit a substantial effect on the 5-year-survival rate. The involvement of epigenetic alterations in the evolution of different cancers has led to the development of epigenetics-based therapies, mainly targeting DNA methyltransferases (DNMTs) and histone-modifying enzymes. So far, their greatest success stories have been registered in hematologic neoplasias. As the effects of epigenetic single agent treatment of solid tumors have been limited, the investigative focus now lies on combination therapies of epigenetically active agents with conventional chemotherapy, immunotherapy, or kinase inhibitors. This review includes a short overview of the most important preclinical approaches as well as an extensive discussion of clinical trials using epigenetic combination therapies in NSCLC, including ongoing trials. Thus, we are providing an overview of what lies ahead in the field of epigenetic combinatory therapies of NSCLC in the coming years.

show abstract

Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy

Cited by 355 publications

References 189 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

Elevated expression of a pharmacologic Polycomb signature predicts poor prognosis in gastric and breast cancer

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

Contact Info

Product

Resources

About