Polycomb group proteins represent a global silencing system involved in development regulation.In specific,they regulate the transition from proliferation to differentiation,contributing to stem-cell maintenance and i...Polycomb group proteins represent a global silencing system involved in development regulation.In specific,they regulate the transition from proliferation to differentiation,contributing to stem-cell maintenance and inhibiting an inappropriate activation of differentiation programs.Enhancer of Zeste Homolog 2(EZH2) is the catalytic subunit of Polycomb repressive complex 2,which induces transcriptional inhibition through the tri-methylation of histone H3,an epigenetic change associated with gene silencing.EZH2 expression is high in precursor cells while its level decreases in differentiated cells.EZH2 is upregulated in various cancers with high levels associated with metastatic cancer and poor prognosis.Indeed,aberrant expression of EZH2 causes the inhibition of several tumor suppressors and differentiation genes,resulting in an uncontrolled proliferation and tumor formation.This editorial explores the role of Polycomb repressive complex 2 in cancer,focusing in particular on EZH2.The canonical function of EZH2 in gene silencing,the non-canonical activities as the methylation of other proteins and the role in gene transcriptional activation,were summarized.Moreover,mutations of EZH2,responsible for an increased methyltransferase activity in cancer,were recapitulated.Finally,various drugs able to inhibit EZH2 with different mechanism were described,specifically underscoring the effects in several cancers,in order to clarify the role of EZH2 and understand if EZH2 blockade could be a new strategy for developing specific therapies or a way to increase sensitivity of cancer cells to standard therapies.展开更多
BACKGROUND Inflammatory bowel disease(IBD)is a prevalent worldwide health problem featured by relapsing,chronic gastrointestinal inflammation.Enhancer of zeste homolog 2(EZH2)is a critical epigenetic regulator in diff...BACKGROUND Inflammatory bowel disease(IBD)is a prevalent worldwide health problem featured by relapsing,chronic gastrointestinal inflammation.Enhancer of zeste homolog 2(EZH2)is a critical epigenetic regulator in different pathological models,such as cancer and inflammation.However,the role of EZH2 in the IBD development is still obscure.AIM To explore the effect of EZH2 on IBD progression and the underlying mechanism.METHODS The IBD mouse model was conducted by adding dextran sodium sulfate(DSS),and the effect of EZH2 on DSS-induced colitis was assessed in the model.The function of EZH2 in regulating apoptosis and permeability was evaluated by Annexin V-FITC Apoptosis Detection Kit,transepithelial electrical resistance analysis,and Western blot analysis of related markers,including Zona occludens 1,claudin-5,and occludin,in NCM460 and fetal human colon(FHC)cells.The mechanical investigation was performed by quantitative reverse transcriptionpolymerase chain reaction,Western blot analysis,and chromatin immunoprecipitation assays.RESULTS The colon length was inhibited in the DSS-treated mice and was enhanced by the EZH2 depletion in the system.DSS treatment caused a decreased histological score in the mice,which was reversed by EZH2 depletion.The inflammatory cytokines,such as tumor necrosis factor-α,interleukin-6,and interleukin-1β,were induced in the DSS-treated mice,in which the depletion of EZH2 could reverse this effect.Moreover,the tumor necrosis factor-αtreatment induced the apoptosis of NCM460 and FHC cells,in which EZH2 depletion could reverse this effect in the cells.Moreover,the depletion of EZH2 attenuated permeability of colonic epithelial cells.Mechanically,the depletion of EZH2 or EZH2 inhibitor GSK343 was able to enhance the expression and the phosphorylation of janus kinase 2(JK2)and signal transducer and activator of transcription in the NCM460 and FHC cells.Specifically,EZH2 inactivated JAK2 expression by regulating histone H3K27me3.JAK2 inhibitor TG101348 was able to reverse EZH2 knockdownmediated colonic epithelial cell permeability and apoptosis.CONCLUSION Thus,we concluded that EZH2 contributed to apoptosis and inflammatory response by inactivating JAK2/signal transducer and activator of transcription signaling in IBD.EZH2 may be applied as a potential target for IBD therapy.展开更多
BACKGROUND Diabetes is a chronic metabolic disease,and a variety of miRNA are involved in the occurrence and development of diabetes.In clinical studies,miR-124 is highly expressed in the serum of patients with diabet...BACKGROUND Diabetes is a chronic metabolic disease,and a variety of miRNA are involved in the occurrence and development of diabetes.In clinical studies,miR-124 is highly expressed in the serum of patients with diabetes and in pancreatic isletβ-cells.However,few reports exist concerning the role and mechanism of action of miR-124 in diabetes.AIM To investigate the expression of miR-124 in diabetic mice and the potential mechanism of action in isletβ-cells.METHODS The expression levels of miR-124 and enhancer of zeste homolog 2(EZH2)in pancreatic tissues of diabetic mice were detected.The targeted relationship between miR-124 and EZH2 was predicted by Targetscan software and verified by a double luciferase reporter assay.Mouse isletβ-cells Min6 were grown in a high glucose(HG)medium to mimic a diabetes model.The insulin secretion,proliferation,cell cycle and apoptosis of HG-induced Min6 cells were detected after interference of miR-124a and/or EZH2.RESULTS The expression of miR-124 was upregulated and EZH2 was downregulated in the pancreatic tissue of diabetic mice compared with control mice,and the expression of miR-124 was negatively correlated with that of EZH2.miR-124 was highly expressed in HG-induced Min6 cells.Inhibition of miR-124 promoted insulin secretion and cell proliferation,induced the transition from the G0/G1 phase to the S phase of the cell cycle,and inhibited cell apoptosis in HG-induced Min6 cells.EZH2 was one of the targets of miR-124.Co-transfection of miR-124 inhibitor and siRNA-EZH2 could reverse the effects of the miR-124 inhibitor in HG-induced Min6 cells.CONCLUSION miR-124 is highly expressed in diabetic mice and HG-induced Min6 cells and regulates insulin secretion,proliferation and apoptosis of isletβ-cells by targeting EZH2.展开更多
文摘Polycomb group proteins represent a global silencing system involved in development regulation.In specific,they regulate the transition from proliferation to differentiation,contributing to stem-cell maintenance and inhibiting an inappropriate activation of differentiation programs.Enhancer of Zeste Homolog 2(EZH2) is the catalytic subunit of Polycomb repressive complex 2,which induces transcriptional inhibition through the tri-methylation of histone H3,an epigenetic change associated with gene silencing.EZH2 expression is high in precursor cells while its level decreases in differentiated cells.EZH2 is upregulated in various cancers with high levels associated with metastatic cancer and poor prognosis.Indeed,aberrant expression of EZH2 causes the inhibition of several tumor suppressors and differentiation genes,resulting in an uncontrolled proliferation and tumor formation.This editorial explores the role of Polycomb repressive complex 2 in cancer,focusing in particular on EZH2.The canonical function of EZH2 in gene silencing,the non-canonical activities as the methylation of other proteins and the role in gene transcriptional activation,were summarized.Moreover,mutations of EZH2,responsible for an increased methyltransferase activity in cancer,were recapitulated.Finally,various drugs able to inhibit EZH2 with different mechanism were described,specifically underscoring the effects in several cancers,in order to clarify the role of EZH2 and understand if EZH2 blockade could be a new strategy for developing specific therapies or a way to increase sensitivity of cancer cells to standard therapies.
基金Supported by National Natural Science Foundation of China,No.81900498.
文摘BACKGROUND Inflammatory bowel disease(IBD)is a prevalent worldwide health problem featured by relapsing,chronic gastrointestinal inflammation.Enhancer of zeste homolog 2(EZH2)is a critical epigenetic regulator in different pathological models,such as cancer and inflammation.However,the role of EZH2 in the IBD development is still obscure.AIM To explore the effect of EZH2 on IBD progression and the underlying mechanism.METHODS The IBD mouse model was conducted by adding dextran sodium sulfate(DSS),and the effect of EZH2 on DSS-induced colitis was assessed in the model.The function of EZH2 in regulating apoptosis and permeability was evaluated by Annexin V-FITC Apoptosis Detection Kit,transepithelial electrical resistance analysis,and Western blot analysis of related markers,including Zona occludens 1,claudin-5,and occludin,in NCM460 and fetal human colon(FHC)cells.The mechanical investigation was performed by quantitative reverse transcriptionpolymerase chain reaction,Western blot analysis,and chromatin immunoprecipitation assays.RESULTS The colon length was inhibited in the DSS-treated mice and was enhanced by the EZH2 depletion in the system.DSS treatment caused a decreased histological score in the mice,which was reversed by EZH2 depletion.The inflammatory cytokines,such as tumor necrosis factor-α,interleukin-6,and interleukin-1β,were induced in the DSS-treated mice,in which the depletion of EZH2 could reverse this effect.Moreover,the tumor necrosis factor-αtreatment induced the apoptosis of NCM460 and FHC cells,in which EZH2 depletion could reverse this effect in the cells.Moreover,the depletion of EZH2 attenuated permeability of colonic epithelial cells.Mechanically,the depletion of EZH2 or EZH2 inhibitor GSK343 was able to enhance the expression and the phosphorylation of janus kinase 2(JK2)and signal transducer and activator of transcription in the NCM460 and FHC cells.Specifically,EZH2 inactivated JAK2 expression by regulating histone H3K27me3.JAK2 inhibitor TG101348 was able to reverse EZH2 knockdownmediated colonic epithelial cell permeability and apoptosis.CONCLUSION Thus,we concluded that EZH2 contributed to apoptosis and inflammatory response by inactivating JAK2/signal transducer and activator of transcription signaling in IBD.EZH2 may be applied as a potential target for IBD therapy.
基金Supported by The Medical Science and Technology Key Project of Henan Province,No.2018020733.
文摘BACKGROUND Diabetes is a chronic metabolic disease,and a variety of miRNA are involved in the occurrence and development of diabetes.In clinical studies,miR-124 is highly expressed in the serum of patients with diabetes and in pancreatic isletβ-cells.However,few reports exist concerning the role and mechanism of action of miR-124 in diabetes.AIM To investigate the expression of miR-124 in diabetic mice and the potential mechanism of action in isletβ-cells.METHODS The expression levels of miR-124 and enhancer of zeste homolog 2(EZH2)in pancreatic tissues of diabetic mice were detected.The targeted relationship between miR-124 and EZH2 was predicted by Targetscan software and verified by a double luciferase reporter assay.Mouse isletβ-cells Min6 were grown in a high glucose(HG)medium to mimic a diabetes model.The insulin secretion,proliferation,cell cycle and apoptosis of HG-induced Min6 cells were detected after interference of miR-124a and/or EZH2.RESULTS The expression of miR-124 was upregulated and EZH2 was downregulated in the pancreatic tissue of diabetic mice compared with control mice,and the expression of miR-124 was negatively correlated with that of EZH2.miR-124 was highly expressed in HG-induced Min6 cells.Inhibition of miR-124 promoted insulin secretion and cell proliferation,induced the transition from the G0/G1 phase to the S phase of the cell cycle,and inhibited cell apoptosis in HG-induced Min6 cells.EZH2 was one of the targets of miR-124.Co-transfection of miR-124 inhibitor and siRNA-EZH2 could reverse the effects of the miR-124 inhibitor in HG-induced Min6 cells.CONCLUSION miR-124 is highly expressed in diabetic mice and HG-induced Min6 cells and regulates insulin secretion,proliferation and apoptosis of isletβ-cells by targeting EZH2.
