EZH2 Emerges as Epigenetic Target

Erin M. Burns, PhD, MSPH
Published: Friday, Sep 22, 2017
Franck Morschhauser MD, PhD
Franck Morschhauser MD, PhD
The disruption of chromatin modulation has been shown to be an important step in the development of certain cancers. A variety of cancer types exhibit chromatin-modifying mutations, which often correlate with cell fate decisions. Specifically, mutations in EZH2 (enhancer of zeste homolog 2) have been frequently observed in cancer, and small molecule inhibitors have been developed against the enzymatic activity of EZH2, with evidence of clinical activity in early-phase trials.

“Some specific cancers are based on ‘gain-of -function’ mutations in EZH2,” noted Thomas M. Kristie, PhD, chief of the Molecular Genetics Section in the Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, in a recent news release.1 “Additionally, it has been proposed that in some cancers, these enzymes repress anti-oncogenes, and treatment with EZH2/1 inhibitors might result in re-expression of these anti-oncogenes.”

The EZH2 gene encodes the protein EZH2, a histone methyltransferase and the core enzymatic subunit of polycomb repressive complex 2 (PRC2), which is involved in chromatin compaction and transcriptional silencing (Figure). EZH2 functions to methylate a lysine residue (K27) on the N-terminal region of histone H3. These activities are part of a emerging class of epigenetic modifiers attracting interest as anticancer targets.

Figure. EZH2’s Role in Promoting Tumors

EZH2s Role in Promoting Tumors
EZH2 overexpression has been associated with enhanced progression and advanced disease in cancers of the prostate, bladder, breast, and endometrium, as well as melanoma. High expression of EZH2, defined as greater than 10% in immunohistochemical analysis and up to 4-fold increased expression via real-time polymerase chain reaction testing, has been associated with increased disease aggressiveness.2 EZH2 has also been implicated in tumor initiation and progression, migration, angiogenesis, stem cell self-renewal, and activated T-regulatory cell functioning.

During development, EZH2/PRC2 has been shown to silence genes associated with alternative fates at specific loci. As in normal stem cells, EZH2 is highly expressed in cancer stem cell populations and suppresses differentiation via repression of lineage-specific factors to maintain these populations. It has been hypothesized that EZH2 blocks differentiation, which facilitates cell transformation.

The retinoblastoma-E2F pathway, which regulates the cell cycle, has been demonstrated to be upstream of EZH2, which is required for proliferative gene expression and E2F-driven proliferation. It is unknown whether any EZH2 targets are essential for EZH2-mediated transformation across all cell types or whether oncogenic changes are cell type-specific.

EZH2 may have a role as a transcriptional coactivator independent of PRC2, leading to direct modulation of transcription factor activity; however, these functions have not been fully elucidated.

Agents in development are highly specific to EZH2 in order to avoid interfering with nontumorigenic pathways. Inhibition of EZH2 methyltransferase activity without degrading the PRC2 complex is achieved through competition with the methyldonor S-adenosyl methionine (SAM) for the EZH2 binding pocket; therefore, these agents are known as SAM-competitive inhibitors.


The small-molecule EZH2 inhibitor most advanced in its development is tazemetostat, which is orally administered (Table). Interim phase II tazemetostat safety data were presented at the 14th International Conference on Malignant Lymphoma in June 2017.3 Tazemetostat was well tolerated and demonstrated clinical activity in early clinical trials of patients with genetically defined solid tumors and hematologic malignancies.


Table. EZH2 Inhibitors in Clinical Development

EZH2 Inhibitors in Clinical Development
Tazemetostat was studied in an open-label multicenter study in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) who received tazemetostat 800 mg twice daily. Grade 3 or higher treatment-emergent adverse events (AEs) were reported in 18% of patients. Any-grade AEs reported in more than 5% of patients included nausea (20%), thrombocytopenia (19%), cough (14%), diarrhea (11%), fatigue (12%), and asthenia (10%).

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