Enhancer of zeste homolog 2 (EZH2), an H3K27-specific histone methyltransferase, has been shown to be frequently overexpressed in various human cancers including lymphoma.
2019; published online January 28, https://doi.org/10.1038/s41588-018-0338-y) examined the effects of mutant EZH2 on the 3D architecture of the lymphoma genome, highlighting the potential relevance of chromatin folding dynamics.
Overexpression and gain-of-function mutations in EZH2 are regarded as oncogenic drivers in lymphoma and other malignancies due to the silencing of tumor suppressors and differentiation genes.
In this review, we present the rationale, key pre-clinical and early clinical findings of small molecule EZH2 inhibitors for use in lymphoma as well as future challenges and potential opportunities for combination therapies.
Here, we critically review the emerging role of EZH2 in malignancies, the development of small molecule inhibitors of EZH2, and their application in lymphoma.
The antitumor efficacy of pharmacological EZH2 inhibition depends on SESTRIN1, indicating that mTORC1 control is a critical function of EZH2 in lymphoma.
These results suggest that Ezh2(Y641F) induces lymphoma and melanoma through a vast reorganization of chromatin structure, inducing both repression and activation of polycomb-regulated loci.
Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex.
New therapeutic approaches targeting aberrant H3K27 methylation include small molecules that block the action of mutant EZH2 in germinal center-derived lymphoma.
These genomic data suggest that targeting the EZH2 MT activity is a valid therapeutic strategy for the treatment of lymphoma patients with EZH2 mutations.
The reduction of CSC self-renewal via EZH2 inhibition offers a potentially attractive therapeutic approach to counter the aberrant activation found in lymphoma and leukemia.
Therefore, our study uncovers an oncogenic role of EZH2 independent of its methyltransferase activity in NKTL and suggests that targeting EZH2 may have therapeutic usefulness in this lymphoma.
EZH2 mediated transcriptional repression through its methyltransferase activity at the chromatin level has certain influence on lymphoma, and there might exist a therapeutic window for the development of new agents and identification of novel diagnostic markers based on EZH2.
Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo.
This represents the first example of a disease-associated gain-of-function mutation in a histone methyltransferase, whereby somatic EZH2 Y641 mutations in lymphoma act dominantly to increase, rather than decrease, histone methylation.