Divergent Effects of EZH1 and EZH2 Protein Expression on the Prognosis of Patients with T-Cell Lymphomas.
Ontology highlight
ABSTRACT:
SUBMITTER: Schumann FL
PROVIDER: S-EPMC8698684 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Polycomb group proteins are critical to maintaining gene repression established during Drosophila development. Part of this group forms the PRC2 complex containing Ez that catalyzes di- and trimethylation of histone H3 lysine 27 (H3K37me2/3), marks repressive to transcription. We report that the mammalian homologs Ezh1 and Ezh2 form similar PRC2 complexes but exhibit contrasting repressive roles. While PRC2-Ezh2 catalyzes H3K27me2/3 and its knockdown affects global H3K27me2/3 levels, PRC2-Ezh1 performs this function weakly. In accordance, Ezh1 knockdown was ineffectual on global H3K27me2/3 levels. Instead, PRC2-Ezh1 directly and robustly represses transcription from chromatinized templates and compacts chromatin in the absence of the methyltransferase cofactor SAM, as evidenced by electron microscopy. Ezh1 targets a subset of Ezh2 genes, yet Ezh1 is more abundant in nonproliferative adult organs while Ezh2 expression is tightly associated with proliferation, as evidenced when analyzing aging mouse kidney. These results might reflect subfunctionalization of a PcG protein during evolution.
| S-EPMC3641558 | biostudies-literature
Project description:Background: Toll-like receptor 4 (TLR4), a member of the pattern recognition receptors, has been reported to be involved in carcinogenesis. However, the clinical impact of TLR4 in peripheral T-cell lymphomas (PTCL) remains unclear. Methods: The current study, using immunohistochemical staining, first examined TLR4 and programmed cell death-ligand 1 (PD-L1) expression in patients with PTCL, to correlate TLR4 and PD-L1 expression with clinicopathological parameters. Results: It was found that the rates of high expression of TLR4 and PD-L1 were 41.7% and 45.8%, respectively. TLR4 expression was closely associated with PD-L1 expression. The expression of TLR4 was closely related to primary extranodal site involvement, increased Ann Arbor stage, and low hemoglobin expression, while the expression of PD-L1 was closely related to a low platelet count and multiple extranodal organ involvements (>1). High expression of either TLR4 or PD-L1 indicated a poor survival rate for patients with PTCL. Multivariate analyses further confirmed that increased expression levels of TLR4 and PD-L1 are unfavorable prognostic factors for PTCL. Conclusion: This study demonstrates that the expressions of TLR4 and PD-L1 are independent predictors of survival time for patients with PTCL. Thus, TLR4 and PD-L1 may serve as potential therapeutic targets in PTCL patients.
| S-EPMC6536125 | biostudies-literature
Project description:While the Polycomb complex is known to regulate cell identity in ES cells, its role in controlling tissue-specific stem cells is not well understood. Here we show that removal of Ezh1 and Ezh2, key Polycomb subunits, from mouse skin results in a marked change in fate determination in epidermal progenitor cells, leading to an increase in the number of lineage-committed Merkel cells, a specialized subtype of skin cells involved in mechanotransduction. By dissecting the genetic mechanism, we showed that the Polycomb complex restricts differentiation of epidermal progenitor cells by repressing the transcription factor Sox2. Ablation of Sox2 results in a dramatic loss of Merkel cells, indicating that Sox2 is a critical regulator of Merkel cell specification. We show that Sox2 directly activates Atoh1, the obligate regulator of Merkel cell differentiation. Concordantly, ablation of Sox2 attenuated the Ezh1/2-null phenotype, confirming the importance of Polycomb-mediated repression of Sox2 in maintaining the epidermal progenitor cell state. Together, these findings define a novel regulatory network by which the Polycomb complex maintains the progenitor cell state and governs differentiation in vivo.
| S-EPMC3715854 | biostudies-literature
Project description:RATIONALE:Polycomb repressive complex 2 is a major epigenetic repressor that deposits methylation on histone H3 on lysine 27 (H3K27me) and controls differentiation and function of many cells, including cardiac myocytes. EZH1 and EZH2 are 2 alternative catalytic subunits with partial functional redundancy. The relative roles of EZH1 and EZH2 in heart development and regeneration are unknown. OBJECTIVE:We compared the roles of EZH1 versus EZH2 in heart development and neonatal heart regeneration. METHODS AND RESULTS:Heart development was normal in Ezh1-/- (Ezh1 knockout) and Ezh2f/f::cTNT-Cre (Ezh2 knockout) embryos. Ablation of both genes in Ezh1-/-::Ezh2f/f::cTNT-Cre embryos caused lethal heart malformations, including hypertrabeculation, compact myocardial hypoplasia, and ventricular septal defect. Epigenome and transcriptome profiling showed that derepressed genes were upregulated in a manner consistent with total EZH dose. In neonatal heart regeneration, Ezh1 was required, but Ezh2 was dispensable. This finding was further supported by rescue experiments: cardiac myocyte-restricted re-expression of EZH1 but not EZH2 restored neonatal heart regeneration in Ezh1 knockout. In myocardial infarction performed outside of the neonatal regenerative window, EZH1 but not EZH2 likewise improved heart function and stimulated cardiac myocyte proliferation. Mechanistically, EZH1 occupied and activated genes related to cardiac growth. CONCLUSIONS:Our work unravels divergent mechanisms of EZH1 in heart development and regeneration, which will empower efforts to overcome epigenetic barriers to heart regeneration.
| S-EPMC5527745 | biostudies-literature
Project description:Enhancer of zeste homolog 2 (EZH2) promotes carcinogenesis by epigenetically silencing tumor suppressor genes. We studied EZH2 expression by immunohistochemistry in a large series of non-small cell lung carcinomas (NSCLC) in association with tumor characteristics and patient outcomes.EZH2 immunohistochemistry expression was analyzed in 265 normal and premalignant bronchial epithelia, 541 primary NSCLCs [221 squamous cell carcinomas (SCC) and 320 adenocarcinomas] and 36 NSCLCs with paired brain metastases. An independent set of 91 adenocarcinomas was also examined. EZH2 expression was statistically correlated with clinico-pathological information, and EGFR/KRAS mutation status.EZH2 expression was significantly (P < 0.0001) higher in SCCs compared with adenocarcinomas and in brain metastasis relative to matched primary tumors (P = 0.0013). EZH2 expression was significantly (P < 0.0001) elevated in bronchial preneoplastic lesions with increasing severity. In adenocarcinomas, higher EZH2 expression significantly correlated with younger age, cigarette smoking, and higher TNM stage (P = 0.02 to P < 0.0001). Higher EZH2 expression in adenocarcinoma was associated with worse recurrence-free survival (RFS; P = 0.025; HR = 1.54) and overall survival (OS; P = 0.0002; HR = 1.96). Furthermore, lung adenocarcinomas with low EZH2 levels and high expression of the lineage-specific transcription factor, TTF-1, exhibited significantly improved RFS (P = 0.009; HR = 0.51) and OS (P = 0.0011; HR = 0.45), which was confirmed in the independent set of 91 adenocarcinomas.In lung, EZH2 expression is involved in early pathogenesis of SCC and correlates with a more aggressive tumor behavior of adenocarcinoma. When EZH2 and TTF-1 expressions are considered together, they serve as a prognostic marker in patients with surgically resected lung adenocarcinomas.
| S-EPMC3890101 | biostudies-literature
Project description:SIX2 (SIX homeobox 2)-positive nephron progenitor cells (NPCs) give rise to all epithelial cell types of the nephron, the filtering unit of the kidney. NPCs have a limited lifespan and are depleted near the time of birth. Epigenetic factors are implicated in the maintenance of organ-restricted progenitors such as NPCs, but the chromatin-based mechanisms are incompletely understood. Here, using a combination of gene targeting, chromatin profiling, and single-cell RNA analysis, we examined the role of the murine histone 3 Lys-27 (H3K27) methyltransferases EZH1 (enhancer of zeste 1) and EZH2 in NPC maintenance. We found that EZH2 expression correlates with NPC growth potential and that EZH2 is the dominant H3K27 methyltransferase in NPCs and epithelial descendants. Surprisingly, NPCs lacking H3K27 trimethylation maintained their progenitor state but cycled slowly, leading to a smaller NPC pool and formation of fewer nephrons. Unlike Ezh2 loss of function, dual inactivation of Ezh1 and Ezh2 triggered overexpression of the transcriptional repressor Hes-related family BHLH transcription factor with YRPW motif 1 (Hey1), down-regulation of Six2, and unscheduled activation of Wnt4-driven differentiation, resulting in early termination of nephrogenesis and severe renal dysgenesis. Double-mutant NPCs also overexpressed the SIX family member Six1 However, in this context, SIX1 failed to maintain NPC stemness. At the chromatin level, EZH1 and EZH2 restricted accessibility to AP-1-binding motifs, and their absence promoted a regulatory landscape akin to differentiated and nonlineage cells. We conclude that EZH2 is required for NPC renewal potential and that tempering of the differentiation program requires cooperation of both EZH1 and EZH2.
| S-EPMC7450110 | biostudies-literature
Project description:EZH2 or EZH1 is the catalytic subunit of the polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). The trimethylation of H3K27 (H3K27me3) is a transcriptionally repressive post-translational modification. Overexpression of EZH2 and hypertrimethylation of H3K27 have been implicated in a number of cancers. Several selective inhibitors of EZH2 have been reported recently. Herein we disclose UNC1999, the first orally bioavailable inhibitor that has high in vitro potency for wild-type and mutant EZH2 as well as EZH1, a closely related H3K27 methyltransferase that shares 96% sequence identity with EZH2 in their respective catalytic domains. UNC1999 was highly selective for EZH2 and EZH1 over a broad range of epigenetic and non-epigenetic targets, competitive with the cofactor SAM and non-competitive with the peptide substrate. This inhibitor potently reduced H3K27me3 levels in cells and selectively killed diffused large B cell lymphoma cell lines harboring the EZH2(Y641N) mutant. Importantly, UNC1999 was orally bioavailable in mice, making this inhibitor a valuable tool for investigating the role of EZH2 and EZH1 in chronic animal studies. We also designed and synthesized UNC2400, a close analogue of UNC1999 with potency >1,000-fold lower than that of UNC1999 as a negative control for cell-based studies. Finally, we created a biotin-tagged UNC1999 (UNC2399), which enriched EZH2 in pull-down studies, and a UNC1999-dye conjugate (UNC2239) for co-localization studies with EZH2 in live cells. Taken together, these compounds represent a set of useful tools for the biomedical community to investigate the role of EZH2 and EZH1 in health and disease.
| S-EPMC3773059 | biostudies-literature
Project description:Resistance to targeted therapies has become increasingly prevalent. We noted that resistance to different targeted therapies occurs by largely common mechanisms. In this study, we used this information for identifying the mechanisms of resistance to enhancer of zeste homolog 2 (EZH2) inhibitors in diffuse large B-cell lymphoma (DLBCL) harboring EZH2 mutations. We discovered that EZH2 inhibitor-resistant DLBCL cells showed activation of the insulin-like growth factor 1 receptor (IGF-1R), MEK, and phosphoinositide-3-kinase (PI3K) pathways. Constitutive activation of IGF-1R, MEK, or PI3K pathways was sufficient to confer resistance to EZH2 inhibitors in DLBCL. The activation of the PI3K/AKT and MAPK pathways decreased TNFSF10 and BAD expression through a FOXO3-dependent mechanism, which was required for the antitumor effects of EZH2i GSK126. We also identified multiple acquired mutations in EZH2 inhibitor-resistant DLBCL cell lines. These mutations independently conferred resistance to EZH2 inhibitors. Mechanistically, cellular thermal shift assays revealed that the acquired EZH2 mutations that confer resistance to EZH2 inhibitors prevent EZH2 inhibitor binding to the EZH2 mutants. Notably, EZH2 inhibitor GSK126- and EPZ-6438-resistant DLBCL cells remained sensitive to the EZH2 inhibitor UNC1999 and embryonic ectoderm development protein inhibitor EED226, which provides an opportunity to treat DLBCLs that are resistant to these drugs. Collectively, our results underpin the importance for developing a unified approach for forestalling drug resistance by prospectively considering lessons learned from the use of different targeted therapeutic agents.
| S-EPMC5946763 | biostudies-literature
Project description:Malignant rhabdoid tumors (MRTs) are rare and highly aggressive pediatric cancers with no standard of care. MRTs are characterized by loss of SMARCB1, which results in upregulated expression of enhancer of zeste homolog 2 (EZH2), which is responsible for the methylation of lysine 27 of histone H3 (H3K27me3), leading to the repression of gene expression. Although previous reports suggest EZH2 as an effective therapeutic target, the functions of EZH1, the other homolog of EZH, in MRT remain unknown. Here, we show that EZH1, as well as EZH2, contributes to MRT cell growth and H3K27 methylation. Depletion or selective inhibition of EZH2 led to a compensatory increase in EZH1 expression, and depletion of EZH1 enhanced the effect of EZH2 inhibition. EZH1/2 dual inhibitors suppressed MRT cell growth markedly, reflecting the reduction of H3K27me3 accumulation at one of the EZH1/2 targets, the CDKN2A locus. Dual inhibition of EZH1/2 in vivo suppressed tumor growth completely, with no significant adverse effects. These findings indicate that both EZH1 and EZH2 are potential targets for MRT therapy, and that EZH1/2 dual inhibitors may be promising therapeutic strategies for MRT.
| S-EPMC9529991 | biostudies-literature
Project description:Purpose: EZH2 and EZH1, the catalytic components of polycomb repressive complex 2 (PRC2), trigger trimethylation of H3K27 (H3K27me3) to repress the transcription of target genes and are implicated in the pathogenesis of various cancers including multiple myeloma and prostate cancer. Here, we investigated the preclinical effects of UNC1999, a dual inhibitor of EZH2 and EZH1, in combination with proteasome inhibitors on multiple myeloma and prostate cancer.Experimental Design:In vitro and in vivo efficacy of UNC1999 and the combination with proteasome inhibitors was evaluated in multiple myeloma cell lines, primary patient cells, and in a xenograft model. RNA-seq and ChIP-seq were performed to uncover the targets of UNC1999 in multiple myeloma. The efficacy of the combination therapy was validated in prostate cancer cell lines.Results: Proteasome inhibitors repressed EZH2 transcription via abrogation of the RB-E2F pathway, thereby sensitizing EZH2-dependent multiple myeloma cells to EZH1 inhibition by UNC1999. Correspondingly, combination of proteasome inhibitors with UNC1999, but not with an EZH2-specific inhibitor, induced synergistic antimyeloma activity in vitro Bortezomib combined with UNC1999 remarkably inhibited the growth of myeloma cells in vivo Comprehensive analyses revealed several direct targets of UNC1999 including the tumor suppressor gene NR4A1 Derepression of NR4A1 by UNC1999 resulted in suppression of MYC, which was enhanced by the combination with bortezomib, suggesting the cooperative blockade of PRC2 function. Notably, this combination also exhibited strong synergy in prostate cancer cells.Conclusions: Our results identify dual inhibition of EZH2 and EZH1 together with proteasome inhibition as a promising epigenetics-based therapy for PRC2-dependent cancers. Clin Cancer Res; 23(16); 4817-30. ©2017 AACR.
| S-EPMC5562278 | biostudies-literature