Basics: Involved in repression of [[transcription]] Regulator of target genes- NGFR (NTRK?) Differentiation Neuro-ectdermal differentiation HDAC inhibitor relevance > [Review: Targeting EZH2 in neuroblastoma (2023)]([https://www.cancertreatmentreviews.com/article/S0305-7372(23)00093-2/fulltext#b0270](https://www.cancertreatmentreviews.com/article/S0305-7372\(23\)00093-2/fulltext#b0270)) > > ![[gr2.jpg]] > Fig. 2 The  enzymatic activity of EZH2 catalyzes trimethylation on H3K27 (H3K27me3), which leads to a conformational change in the structure of chromatin and repression of transcription. > > (...) In addition, EZH2 can also play a non-canonical role in the PRC2-independent pathway as a transcriptional activator through interaction with the estrogen receptor (ER) and b-catenin in ER-positive luminal like MCF-7 cells or activate NFkB genes by forming a ternary complex with RelA and RelB in ER-negative MDA-MB-231 cells [36](https://www.cancertreatmentreviews.com/article/S0305-7372\(23\)00093-2/fulltext#b0180). > > These studies indicate EZH2 functions as either a transcriptional repressor or activator depending on tumor cell type and through a PRC2-dependent or independent pathway. > > (...) In these studies, EZH2 overexpression is thought to repress tumor suppressor genes through its improved enzymatic activity of trimethylation H3K27, promoting oncogenesis. Key tumor suppressor genes identified as being repressed by overexpression of EZH2 include WNT agonist DKK1, angiogenesis factor VASH1 and cell cycle regulator, p16/CDKN2A [[[42]](https://www.cancertreatmentreviews.com/article/S0305-7372\(23\)00093-2/fulltext#b0210)]. > > <span style="background:#fff88f">However, several studies have also suggested two other mechanisms by which EZH2 may promote of oncogenesis. For example, Richter et al. found that EZH2 promotes oncogenesis and a stem cell like phenotype in Ewing tumors via increased EZH2 expression as a result of transcriptional activation by the EWS/FLI1 fusion protein at the _EZH2_ promoter</span> [43](https://www.cancertreatmentreviews.com/article/S0305-7372\(23\)00093-2/fulltext#b0215). >[!Abstract]+ EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation [(PNAS 2009)](https://pmc.ncbi.nlm.nih.gov/articles/PMC2656557/) > >EZH2-mediated gene silencing was shown to be dependent on histone deacetylase (HDAC) activity. Subsequent microarray analysis of EZH2 knock down, HDAC-inhibitor treatment and confirmation in independent assays revealed an undifferentiated phenotype maintained by EZH2 in ET. EZH2 regulated stemness genes such as nerve growth factor receptor (NGFR), as well as genes involved in neuroectodermal and endothelial differentiation (EMP1, EPHB2, GFAP, and GAP43). These data suggest that EZH2 might have a central role in ET pathology by shaping the oncogenicity and stem cell phenotype of this tumor. Upregulated / Downregulated / Other in DSRCT? ## What is it Seems to be epigenetic related. Migration, TME, etc EZH2 identified in DSRCT PDX model paper Therapeutic Potential of NTRK3 Inhibition in Desmoplastic Small Round Cell Tumor [(2020)](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212565/) ![[nihms-1649687-f0001.jpg]] #### Alteration of the TME in Ewing's Sarcoma via EZH2 gene in Extracellular Vesicles > Ewing sarcoma EVs could also further influence CAF phenotypes and promote cancer progression. One of the components of EwS EVs, _EZH2_ transcripts, could potentially alter CAFs, after EV uptake ([Miller et al., 2013](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B89)). In systemic sclerosis (scleroderma), increased levels of EZH2 was detected in dermal fibroblasts, leading to an increased migratory ability ([Tsou et al., 2019](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B134)). Meanwhile, treatment of dermal fibroblasts with DZNep, an EZH2 inhibitor, decreased the expression of genes involved in fibrosis and altered the DNA methylation states of 37 CpG sites in 24 genes ([Tsou et al., 2019](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B134)). Similarly, transfer of _EZH2_ transcripts from EwS EVs could increase the level of expression of EZH2 in CAFs, enhancing their ability to migrate. Hence, EwS EVs may potentially convert fibroblasts into CAFs, supporting growth of cancer cells by secreting growth factors and cytokines such as IL-6 known to increase EwS resistance to apoptosis in a paracrine manner ([Xing et al., 2010](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B153); [Lissat et al., 2015](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B80)). EwS EVs could allow CAFs to migrate away from EwS cells, converting surrounding areas into a more growth-permissive environment with growth factors and cytokines, priming the conditions for EwS cells to expand locally. ... > _EZH2_ transcripts in EwS EVs could also alter T cells in the TME ([Miller et al., 2013](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B89)). When EZH2 is absent or inhibited in regulatory T cells, their ability to suppress effector T cells was blocked, increasing intratumoral levels of effector T cells, and reducing tumor growth ([Goswami et al., 2018](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B38); [Wang et al., 2018](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B146)). In addition, inhibition of EZH2 in effector T cells promoted their differentiation and increased their cytotoxicity, resulting in a stronger immune response against cancer cells ([Yang X.-P. et al., 2015](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B157); [Goswami et al., 2018](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B38)). These results suggest that the EwS EV-mediated transfer of _EZH2_ transcripts may increase the levels of EZH2 in regulatory T cells, thereby compromising immune response effectiveness. For effector T cells, increased levels of EZH2 may suppress their differentiation and cytotoxic functions. Overall, EwS EVs may potentially be involved in the immunosuppression of T cells ([Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/figure/F2/)). ... > The production of specific cytokines by TAMs could be triggered by EwS EVs and promote tumor growth. Following EwS EV uptake, the potential upregulation of EZH2 in TAMs and its subsequent H3K27me3 activity may facilitate macrophage activation by mediating the interferon gamma-induced repression of anti-inflammatory genes, leading to MyD88-dependent proinflammatory responses ([Qiao et al., 2016](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B102); [Zhang et al., 2018](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B162)). In _Xenopus_ cells, overexpression of dickkopf homolog 2 (DKK2) synergizes with the co-expressed Lrp6 to increase Wnt/β-catenin signaling, initiating a proinflammatory response activation and TAM differentiation into a M2 phenotype ([Brott and Sokol, 2002](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B12); [Bergenfelz et al., 2012](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B9); [Naskar et al., 2014](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B93)). Similarly, DKK2 upregulation by EwS EVs ([Staege et al., 2004](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B122); [Miller et al., 2013](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B89)) may also lead to Wnt5 signaling activation in cells with high levels of Lrp6. Wnt5a induces an immunosuppressive phenotype in macrophages, in which the NF-κB pathway is inhibited and anti-inflammatory cytokine IL-10 is secreted ([Bergenfelz et al., 2012](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B9)). Since IL-10 is associated with immunosuppression ([Saraiva and O’Garra, 2010](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B109)), these findings suggest that the presence of these transcripts in EwS EVs may modulate the repertoire of cytokines produced by TAMs, to reach a fine balance that allows immunosuppression ([Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/figure/F2/)). > Dendritic Cells in the TME > > Furthermore, EZH2 from EwS EVs is potentially oncogenic as it was shown to promote DC neoplasms through EZH2 regulation of adhesion dynamics along with the p-ERK1/2 signaling cascade ([Miller et al., 2013](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B89); [Tian et al., 2018](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B127)). EZH2 is also involved in DC migration and survival, since its deficiency in mice models impaired adhesion-complex formation and suppressed autoimmune encephalomyelitis, highlighting its complex regulatory role in DCs ([Gunawan et al., 2015](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/#B45)). As DCs in the TME of EwS may take up the contents of EwS EVs, increased levels of PRKCB and EZH2 expression could potentially initiate abnormal DCs differentiation in the TME and suppress immune response ([Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484747/figure/F2/)), thus warranting further investigation to elucidate the possible interactions between TME DCs and EwS cells via EwS EVs. #### Bone Mets - Futile but FAK Focal Adhesion Kinase inhibitors impedes Mets > It should be noted that not all tumors respond well to EZH2 inhibition. As over 50% of stage 3 and stage 4 breast cancer patients suffer from bone metastases, Dihua Yu et al. found that EZH2 inhibitor was futile to bone metastasis. However, treatment with focal adhesion kinase inhibitor, a downstream effector of EZH2 of breast cancer bone metastasis, significantly impedes the metastasis [[27](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10281724/#b27-jfda212-231)]. From [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10281724/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10281724/) #### Care > However, EZH2 and lysine methylation can have tumor suppressing activity, for example in [myelodysplastic syndrome](https://en.wikipedia.org/wiki/Myelodysplastic_syndrome "Myelodysplastic syndrome"),[49](https://en.wikipedia.org/wiki/EZH2#cite_note-pmid20601954-49) indicating that EZH2 inhibition may not be beneficial in all cases. #### Potential treatment options Tazemetostat? Tazemetostat is a cancer drug that acts as a potent selective [EZH2](https://en.wikipedia.org/wiki/EZH2 "EZH2")[inhibitor](https://en.wikipedia.org/wiki/Enzyme_inhibitor "Enzyme inhibitor").[2](https://en.wikipedia.org/wiki/Tazemetostat#cite_note-2) Tazemetostat blocks activity of the EZH2 methyltransferase, which may help keep the cancer cells from growing.[1](https://en.wikipedia.org/wiki/Tazemetostat#cite_note-FDA_PR-1) According to the NCI Drug Dictionary, "tazemetostat is an orally available, small molecule selective and S-adenosyl methionine (SAM) competitive inhibitor of histone methyl transferase EZH2, with potential antineoplastic activity. Upon oral administration, tazemetostat selectively inhibits the activity of both wild-type and mutated forms of EZH2. Inhibition of EZH2 specifically prevents the methylation of histone H3 [lysine](https://en.wikipedia.org/wiki/Lysine "Lysine") 27 (H3K27). This decrease in histone methylation alters gene expression patterns associated with cancer pathways and results in decreased tumor cell proliferation in EZH2 mutated cancer cells. EZH2, which belongs to the class of histone methyltransferases (HMTs), is overexpressed or mutated in a variety of cancer cells and plays a key role in [tumor](https://en.wikipedia.org/wiki/Tumor "Tumor") cell proliferation."[3](https://en.wikipedia.org/wiki/Tazemetostat#cite_note-3) The most common side effects are pain, fatigue, nausea, decreased appetite, vomiting and constipation.[1](https://en.wikipedia.org/wiki/Tazemetostat#cite_note-FDA_PR-1) People taking tazemetostat are at increased risk of developing secondary malignancies including: T-cell lymphoblastic lymphoma (a type of blood cancer that affects the lymphatic system usually found in the lymph nodes), myelodysplastic syndrome (a disorder resulting from poorly formed or dysfunctional blood cells) and acute myeloid leukemia (a cancer of the blood and bone marrow).[1](https://en.wikipedia.org/wiki/Tazemetostat#cite_note-FDA_PR-1)