Wedelolactone Targets EZH2-mediated Histone H3K27 Methylation in Mantle Cell Lymphoma

Romanchikova, Nadezhda; Trapencieris, Pēteris

doi:10.21873/anticanres.13577

Cited by 14 publications

(8 citation statements)

References 27 publications

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“… 29 WEL targeted EZH2-mediated histone H3K27 methylation in mantle cell lymphoma. 26 In the present study, loss of PTPN2 aggravated HK-2 cell damage via elevating the production of inﬂammatory cytokines and promoting apoptosis in the presence of LPS and WEL. Hence, elevating the levels of PTPN2 may be an effective therapeutic method for the treatment of LPS-induced renal injury.…”

Section: Discussionsupporting

confidence: 47%

Wedelolactone improves the renal injury induced by lipopolysaccharide in HK-2 cells by upregulation of protein tyrosine phosphatase non-receptor type 2

et al. 2021

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Objective To explore the effects of wedelolactone (WEL) on sepsis-induced renal injury in the human renal proximal tubular epithelial cell line HK-2. Methods HK-2 cells were stimulated by 1 µg/ml lipopolysaccharide (LPS) to trigger renal injury in vitro. HK-2 cells were pretreated with or without WEL (0.1, 1 and 10 µM) before LPS stimulation. Protein and mRNA analyses were performed using enzyme-linked immunosorbent assays, Western blot analysis and quantitative reverse transcription–polymerase chain reaction. The MTT assay and flow cytometry were used to measure cell viability and the rate of cell apoptosis. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) knockdown was induced by the transection of HK-2 cells with short hairpin RNA. Results Cell viability was significantly increased in a dose-dependent manner by WEL in LPS-induced HK-2 cells. WEL also decreased the levels of four inflammatory cytokines and cell apoptosis in LPS-induced HK-2 cells. The level of PTPN2 was increased after WEL treatment. PTPN2 knockdown partly abolished the inhibitory effects of WEL on cell apoptosis, the levels of inflammatory cytokines and on p38 mitogen-activated protein kinase/nuclear factor-kappaB signalling in LPS-induced HK-2 cells. Conclusion WEL improved renal injury by suppressing inflammation and cell apoptosis through upregulating PTPN2 in HK-2 cells. PTPN2 might be used as a potential therapeutic target for LPS-induced sepsis.

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Section: Discussionsupporting

confidence: 47%

Wedelolactone improves the renal injury induced by lipopolysaccharide in HK-2 cells by upregulation of protein tyrosine phosphatase non-receptor type 2

et al. 2021

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“…EZH2 is expression is low in the normal liver, and is associated with methylation of histone H3K27 and recruitment of methyltransferases, which are involved in DNA replication for cancer progression, and stem cell maintenance and differentiation of other cell lineages, such as immune cells (32,33). Several studies have confirmed its prognostic value and importance in various types of cancer, including lymphoma, glioma, head and neck carcinoma, and cervical neoplasia (34)(35)(36)(37)(38). Novel therapeutic methods have been developed to target EZH2, although high expression of EZH2 is not always correlated with the malignancy of a cancer, such as in colorectal cancer (39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Immune system‑associated genes increase malignant progression and can be used to predict clinical outcome in patients with hepatocellular carcinoma

Huang

Chen

et al. 2020

Int J Oncol

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Hepatocellular carcinoma (HCC) is one of the most malignant types of cancer, and is associated with high recurrence rates and a poor response to chemotherapy. Immune signatures in the microenvironment of HCC have not been well explored systematically. The aim of the present study was to identify prognostic immune signatures and build a nomogram for use in clinical evaluation. Using bioinformatics analysis, RNA-seq data and overall survival (OS) information on 370 HCC cases from TCGA and 232 HCC cases from ICGC were analyzed. The differential expression of select immune genes, based on previously published studies, between HCC and adjacent tissue were analyzed using the limma package in R. Enrichment of pathways and gene ontology analysis was performed using clusterProfiler. Subsequently, univariate Cox regression analysis, Lasso penalty linear regression and multivariate Cox regression models were used to construct a model for immune risk score (IRS). The R packages, survival and survivalROC, were used to plot survival and the associated receiver operating characteristic curves. Infiltration of immune cells was calculated using Tumor IMmune Estimation Resource, with significance examined using a Pearson's correlation test. P<0.05 was considered significant. Based on the analysis, expression of 200 immune genes were upregulated and 47 immune genes were downregulated immune genes. In the multivariate Cox model, 5 genes (enhancer of zest homology 2, ferritin light chain, complement factor H related 3, isthmin 2, cyclin dependent kinase 5) were used to generate the IRS. By stratifying according to the median IRS, it was shown that patients with a high IRS had poor OS rates after 1, 2, 3 and 5 years, and this result was consistent across the testing, training and independent validation cohorts. Additionally, the IRS was correlated with the abundance of infiltrating immune cells. The nomogram built using IRS and clinical characteristics, was able to predict 1, 3 and 5 year OS with area under the curve values of >0.8. These results suggest that the model developed to calculate the IRS may be used to monitor the effectiveness of treatment strategies and for prognostic prediction.

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“…In an effort to understand the mechanism of action, we found that inhibition of EZH2 by chidemide or shEZH2 decreased expression of H3K27me3 and DNMT3A, and increased cytotoxic sensitivity in AML cells and stem/progenitor cells. EZH2 is a histone methyltransferase associated with transcriptional repression through dimethylation and trimethylation of H3K27 (H3K27me2/3), and EZH2 mediated H3K27 methylation contributes to pathological process and poor prognosis in hematological malignancies [57,58]. Depletion of EZH2 suppresses the expression of H3K27me3, and inhibits survival of LSC in mixed lineage leukemia [59].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of EZH2 by chidamide exerts antileukemia activity and increases chemosensitivity through Smo/Gli-1 pathway in acute myeloid leukemia

Jiang

Cheng

et al. 2020

Preprint

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Background: Dysregulation of epigenetics plays important roles in leukemogenesis and progression of acute myeloid leukemia (AML). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) reciprocally regulate acetylation and deacetylation of nuclear histone, aberrant activation of HDAC results in uncontrolled proliferation and differentiated blockage, HDAC inhibitors have been investigated as therapeutic drugs for treatment of AML. Methods: Cell growth was assessed by CCK-8 assay, apoptosis was determined by flow cytometry in AML cell lines, CD45+ and CD34+CD38- cells from patient’s samples after stained with Annexin V-fluorescein isothiocyanate (FITC)/Propidium Iodide (PI). EZH2 expression was silenced by short hairpin RNA (shRNA). The pathway changes were detected by western blot. The effect of chidamide or EZH2 shRNA in combination with adriamycin was studies in vivo in nude mice model bearing leukemia.Results: In this study, we investigated the antileukemia activities of HDAC inhibitor chidamide and its combinatorial effect with cytotoxic agent in AML. We demonstrated in vitro and in vivo that chidamide suppressed expression of EZH2, exerted potential antileukemia activity and increased the sensitivity AML cells and AML stem/progenitor cells to chemotherapeutic drug through Smo/Gli-1 pathway. In addition to decrease the expression of H3K27me3 and DNMT3A, inhibition of EZH2 either pharmacologicall by chidamide or genetically by shEZH2 decreased the activity of Smo/Gli-1 pathway, and increased chemotherapeutic sensitivity in AML cells. Conclusions: Inhibition of EZH2 by chidamide has antileukemia activity and increases chemosensitivity, it provides a potential strategy to improve chemotherapeutic effect in AML.

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Wedelolactone Targets EZH2-mediated Histone H3K27 Methylation in Mantle Cell Lymphoma

Cited by 14 publications

References 27 publications

Wedelolactone improves the renal injury induced by lipopolysaccharide in HK-2 cells by upregulation of protein tyrosine phosphatase non-receptor type 2

Wedelolactone improves the renal injury induced by lipopolysaccharide in HK-2 cells by upregulation of protein tyrosine phosphatase non-receptor type 2

Immune system‑associated genes increase malignant progression and can be used to predict clinical outcome in patients with hepatocellular carcinoma

Inhibition of EZH2 by chidamide exerts antileukemia activity and increases chemosensitivity through Smo/Gli-1 pathway in acute myeloid leukemia

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