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Enhancer of zeste homolog 2 (EZH2) is enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2) that can alter downstream target genes expression by trimethylation of Lys-27 in histone 3 (H3K27me3). EZH2 could also regulate gene expression in ways besides H3K27me3. Functions of EZH2 in cells proliferation, apoptosis, and senescence have been identified. Its important roles in the pathophysiology of cancer are now widely concerned. Therefore, targeting EZH2 for cancer therapy is a hot research topic now and different types of EZH2 inhibitors have been developed. In this review, we summarize the structure and action modes of EZH2, focusing on up-to-date findings regarding the role of EZH2 in cancer initiation, progression, metastasis, metabolism, drug resistance, and immunity regulation. Furtherly, we highlight the advance of targeting EZH2 therapies in experiments and clinical studies.

EZH2 inhibitors (EZH2i), a class of small-molecule inhibitors that target EZH2 to exert anti-tumor functions, have just been approved by the US Food and Drug Administration (FDA) in treatment of adults and adolescents with locally advanced or metastatic epithelioid sarcoma. The application of EZH2i in several solid tumors is still in different stages of clinical trials and needs to be further validated. As a key epigenetic regulator, besides its role in controlling the proliferation of tumor cells, EZH2 has been implicated in the regulation of various immune cells including macrophages. But there are still controversial research results at present. Colorectal cancer (CRC) is a common malignant tumor that highly expresses EZH2, which has the third highest incidence and is the second leading cause of cancer-related death worldwide. Studies have shown that the numbers of M2-type tumor-associated macrophages (TAMs) are highly associated with the progression and metastasis of CRC. In the current study, we aim to investigate how EZH2 modulates the polarization of macrophages in the tumor microenvironment (TME) of CRC, and compare the role of two different EZH2 inhibitors, EPZ6438 and GSK126. We applied a 3D culture method to demonstrate that EZH2i did indeed suppress the proliferation of CRC cells in vitro . In vivo , we found that the percentage of CD206 + macrophages of the TME was decreased under the treatment of EPZ6438, but it increased upon GSK126 treatment. Besides, in the co-culture system of macrophages and CRC cells, EPZ6438 led to significant elevation of M1 markers and reduction of M2 markers. Furthermore, mechanistic studies validated by ChIP-qPCR demonstrated that EZH2i inhibit EZH2-mediated H3K27me3 levels on the promoters of STAT3, an essential transcription factor for M1 macrophage polarization. Therefore, our data suggested that EZH2i not only suppress CRC cell proliferation directly, but also regulate macrophage by skewing M2 into effector M1 macrophage to exert a tumor suppressive effect. Moreover, our study provided new insight for better understanding of the role of two kinds of EZH2i: EPZ6438 and GSK126, which may pave the way in treating CRC by targeting cancer cells and immune cells via this epigenetic approach in the future.

Immune dysfunction in the tumor microenvironment occurs through epigenetic changes in both tumor cells and immune cells that alter transcriptional programs driving cell fate and cell function. Oncogenic activation of the histone methyltransferase EZH2 mediates gene expression changes, governing tumor immunogenicity as well as differentiation, survival and activation states of immune lineages. Emerging preclinical studies have highlighted the potential for EZH2 inhibitors to reverse epigenetic immune suppression in tumors and combine with immune checkpoint therapies. However, EZH2 activity is essential for the development of lymphoid cells, performing critical immune effector functions within tumors. In this review, we highlight the complexity of EZH2 function in immune regulation which may impact the implementation of combination with immunotherapy agents in clinic.

EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which along with other PRC2 components mediates gene expression suppression via the methylation of Histone H3 at lysine 27. Recent studies have revealed a dichotomous role of EZH2 in physiology and in the pathogenesis of cancer. While it plays an essential role in the development of the lymphoid system, its deregulation, whether due to genetic or non-genetic causes, promotes B cell- and T cell-related lymphoma or leukemia. These findings triggered a boom in the development of therapeutic EZH2 inhibitors in recent years. Here, we discuss physiologic and pathogenic function of EZH2 in lymphoid context, various internal causes of EZH2 aberrance and how EZH2 modulates lymphomagenesis through epigenetic silencing, post-translational modifications (PTMs), orchestrating with surrounding tumor micro-environment and associating with RNA or viral partners. We also summarize different strategies to directly inhibit PRC2-EZH2 or to intervene EZH2 upstream signaling.

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) to regulate gene expression through epigenetic machinery. EZH2 functions as a double-facet molecule in regulation of gene expression via repression or activation mechanisms, depending on the different cellular contexts. EZH2 interacts with both histone and non-histone proteins to modulate diverse physiological functions including cancer progression and malignancy. In this review article, we focused on the updated information regarding microRNAs (miRNAs) and long non coding RNAs (lncRNAs) in regulation of EZH2, the oncogenic and tumor suppressive roles of EZH2 in cancer progression and malignancy, as well as current pre-clinical and clinical trials of EZH2 inhibitors.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death. The accumulation of genetic and epigenetic changes is closely related to the occurrence and development of HCC. Enhancer of zeste homolog 2 (EZH2, a histone methyltransferase) is suggested to be one of the principal factors that mediates oncogenesis by acting as a driver of epigenetic alternation. Recent studies show that EZH2 is widely involved in proliferation and metastasis of HCC cells. In this review, the functions of EZH2 in HCC progression, the role of EZH2 in tumor immunity and the application of EZH2-related inhibitors in HCC therapy are summarized.

Diosgenin, a natural steroidal saponin isolated from , has been reported to exert anti-cancer effects. Inhibitors of enhancer of zeste homology 2 (EZH2) have been widely used in treatment of cancers. However, the effects of combined treatment with diosgenin and an EZH2 inhibitor on gastric cancer (GC) cells, and the mechanism for those effects are not fully understood. AGS and SGC-7901 gastric cancer cells were treated with diosgenin (0 to 8 μM), followed by treatment with either diosgenin or an EZH2 inhibitor, GSK126 alone. Afterwards, an EZH2 overexpression plasmid and Rho inhibitor, GSK429286A was involved in cells. Cell proliferation, cell cycle distribution, and cell apoptosis, migration, and invasion were examined by CCK-8 assays, flow cytometry, and transwell assays. Western blotting was performed to detect the relative levels of protein expression. Treatment with diosgenin alone caused a dose-dependent decrease in the cell viability, and combined treatment with an EZH2 inhibitor plus GSK126 caused a further significant decrease. A further analysis revealed that treatment with either diosgenin or GSK126 alone induced significant increases in G0/G1 cell cycle arrest and apoptosis, and combined treatment with both agents induced further increases in those parameters. In addition, combined treatment with diosgenin and GSK126 synergistically induced even stronger effects on impaired cell proliferation, G0/G1 phase arrest, and cell apoptosis when compared to treatment with either diosgenin or GSK126 treatment alone. At the molecular level, we demonstrated that inhibition of Rho/ROCK signaling by combined treatment with diosgenin and GSK126 could downregulate the expression of epithelial-mesenchymal transition (EMT)-related molecules. We also found that EZH2 overexpression reversed the anti-tumor effect of diosgenin by inducing cell survival, blocking G1-phase arrest, and promoted EMT. While, these biological properties were further reversed by GSK429286A. Collectively, combined treatment with diosgenin and GSK126 produced even more significant effects on GC cell inhibition by targeting EZH2 via Rho/ROCK signaling-mediated EMT, which might be a therapeutic strategy for improving the poor therapeutic outcomes obtained with GSK126 monotherapy.

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is overexpressed in a variety of malignancies including prostate cancer (PCa) and may play important roles in tumor progression. Gene copy number gains, enhanced transcription, and a few circRNAs have been reported to upregulate EZH2. It was not known whether EZH2 itself generates circRNAs that promote its own expression. We here report the identification of circEZH2E2/E3 that is derived from exons 2 and 3 of the EZH2 gene and overexpressed in PCa. We show that circEZH2E2/E3 functions as a dual inhibitor for both miR363 and miR708 that target the EZH2 3′UTR and CDS, respectively, resulting in the upregulation of EZH2 expression and hence the downregulation of EZH2‐repressed genes (e.g., CDH1 and DAB2IP), and enhancement of PCa cell proliferation, migration, invasion, and xenograft PCa growth. Overexpression of circEZH2E2/E3 is significantly correlated with higher tumor grade, tumor progression, and unfavorable progression‐free and disease‐specific survival in PCa patients. These findings show a novel autoenhancing EZH2–circEZH2E2/E3‐miR363/miR708–EZH2 regulatory loop, by which circEZH2E2/E3 plays important roles in PCa tumorigenesis and progression by upregulating EZH2, and may have potential diagnostic, prognostic, and therapeutic uses in PCa management. The EZH2‐derived circEZH2E2/E3 functions as a dual suppressor of both miR363 and miR708 by competitively binding to miRNAs and blocking their inhibitory effects on EZH2 expression, resulting in EZH2 overexpression, which in turn inhibits transcription of downstream tumor‐suppressive genes such as E‐cadherin and DAB2IP and promotes prostate cancer cell growth and tumor progression.

The histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2), a component of the polycomb group complex, is vital for stem cell development, including hematopoiesis. Its primary function, to deposit the histone mark H3K27me3, promotes transcriptional repression. The activity of EZH2 influences cell fate regulation, namely the balance between self-renewal and differentiation. The contribution of aberrant EZH2 expression to tumorigenesis by directing cells toward a cancer stem cell (CSC) state is increasingly recognized. However, its role in hematological malignancies is complex. Point mutations, resulting in gain-of-function, and inactivating mutations, reported in lymphoma and leukemia, respectively, suggest that EZH2 may serve a dual purpose as an oncogene and tumor-suppressor gene. 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. The discovery of small molecules that specifically inhibit EZH2 raises the exciting possibility of exploiting the oncogenic addiction of tumor cells toward this protein. However, interference with the tumor-suppressor role of wild-type EZH2 must be avoided. This review examines the role of EZH2 in normal and malignant hematopoiesis and recent developments in harnessing the therapeutic potential of EZH2 inhibition.

CRISPR/Cas9 system has become a promising gene editing tool for cancer treatment. However, development of a simple and effective nanocarrier to incorporate CRISPR/Cas9 system and chemotherapeutic drugs to concurrently tackle the biological safety and packaging capacity of viral vectors and combine gene editing-chemo for cancer therapy still remains challenges. Herein, a chain-shattering Pt(IV)-backboned polymeric nanoplatform is developed for the delivery of EZH2-targeted CRISPR/Cas9 system (NP CSPt/pEZH2 ) and synergistic treatment of prostate cancer. The pEZH2/Pt(II) could be effectively triggered to unpack/release from NP CSPt/pEZH2 in a chain-shattering manner in cancer cells. The EZH2 gene disruption efficiency could be achieved up to 32.2% of PC-3 cells in vitro and 21.3% of tumor tissues in vivo , leading to effective suppression of EZH2 protein expression. Moreover, significant H3K27me3 downregulation could occur after EZH2 suppression, resulting in a more permissive chromatin structure that increases the accessibility of released Pt(II) to nuclear DNA for enhanced apoptosis. Taken together, substantial proliferation inhibition of prostate cancer cells and further 85.4% growth repression against subcutaneous xenograft tumor could be achieved. This chain-shattering Pt(IV)-backboned polymeric nanoplatform system not only provides a prospective nanocarrier for CRISPR/Cas9 system delivery, but also broadens the potential of combining gene editing-chemo synergistic cancer therapy.