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
多聚梳抑制复合体2作为一种表观遗传调节因子可选择性催化组蛋白H3第27位赖氨酸三甲基化,从而诱导靶基因转录抑制。Zeste基因增强子同源物2(enhancer of zeste homolog 2,EZH2)是多聚梳抑制复合体2中具有酶活性的亚基,在肿瘤触发、进展...多聚梳抑制复合体2作为一种表观遗传调节因子可选择性催化组蛋白H3第27位赖氨酸三甲基化,从而诱导靶基因转录抑制。Zeste基因增强子同源物2(enhancer of zeste homolog 2,EZH2)是多聚梳抑制复合体2中具有酶活性的亚基,在肿瘤触发、进展、转移及耐药性方面有重要作用。EZH2与其他表观遗传修饰酶相互协调介导基因沉默,EZH2超表达是多种实体肿瘤晚期和转移性的标志,EZH2的表达与活性受多种肿瘤相关转录因子的调节,各位点氨基酸残基的磷酸化状态可影响EZH2的催化活性,EZH2基因突变在血液系统恶性肿瘤中频繁发生,除通过经典作用即催化抑癌基因启动子区组蛋白H3第27位赖氨酸甲基化来抑制转录外,EZH2还具有诱导基因活化功能。因此,EZH2成为肿瘤治疗的一个理想靶点,其特异性抑制剂EPZ6438正处于临床Ⅰ/Ⅱ期试验阶段。展开更多
卵巢癌是女性生殖系统常见的恶性肿瘤,由于其发病隐匿,大部分患者在确诊时已处于晚期,已成为致死率最高的妇科肿瘤。因此,寻找特异的分子标志物及有效的分子靶点对卵巢癌的诊断、疗效评估、预后判断及治疗等具有重要的意义。研究表明,...卵巢癌是女性生殖系统常见的恶性肿瘤,由于其发病隐匿,大部分患者在确诊时已处于晚期,已成为致死率最高的妇科肿瘤。因此,寻找特异的分子标志物及有效的分子靶点对卵巢癌的诊断、疗效评估、预后判断及治疗等具有重要的意义。研究表明,表观遗传修饰在卵巢癌的发生、发展中起着关键作用。组蛋白甲基转移酶Zeste同源蛋白2增强子(enhancer of zeste homolog 2,EZH2)是多梳抑制复合体2(PRC2)的酶催化亚基,可通过对核小体组蛋白H3的27位赖氨酸(H3K27)进行甲基化修饰,进而导致下游靶基因的沉默,在细胞凋亡、细胞周期及细胞分化等重要生物学过程中发挥重要作用。现有研究表明EZH2在卵巢恶性肿瘤中高表达,其表达水平与卵巢癌患者的化疗疗效及预后密切相关。此外,EZH2作为表观遗传修饰因子,影响卵巢癌细胞的增殖、转移及耐药等生物学行为,在肿瘤进展中发挥重要的调控作用。因此,EZH2可能成为卵巢恶性肿瘤有效的治疗新靶点。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.
文摘多聚梳抑制复合体2作为一种表观遗传调节因子可选择性催化组蛋白H3第27位赖氨酸三甲基化,从而诱导靶基因转录抑制。Zeste基因增强子同源物2(enhancer of zeste homolog 2,EZH2)是多聚梳抑制复合体2中具有酶活性的亚基,在肿瘤触发、进展、转移及耐药性方面有重要作用。EZH2与其他表观遗传修饰酶相互协调介导基因沉默,EZH2超表达是多种实体肿瘤晚期和转移性的标志,EZH2的表达与活性受多种肿瘤相关转录因子的调节,各位点氨基酸残基的磷酸化状态可影响EZH2的催化活性,EZH2基因突变在血液系统恶性肿瘤中频繁发生,除通过经典作用即催化抑癌基因启动子区组蛋白H3第27位赖氨酸甲基化来抑制转录外,EZH2还具有诱导基因活化功能。因此,EZH2成为肿瘤治疗的一个理想靶点,其特异性抑制剂EPZ6438正处于临床Ⅰ/Ⅱ期试验阶段。
文摘卵巢癌是女性生殖系统常见的恶性肿瘤,由于其发病隐匿,大部分患者在确诊时已处于晚期,已成为致死率最高的妇科肿瘤。因此,寻找特异的分子标志物及有效的分子靶点对卵巢癌的诊断、疗效评估、预后判断及治疗等具有重要的意义。研究表明,表观遗传修饰在卵巢癌的发生、发展中起着关键作用。组蛋白甲基转移酶Zeste同源蛋白2增强子(enhancer of zeste homolog 2,EZH2)是多梳抑制复合体2(PRC2)的酶催化亚基,可通过对核小体组蛋白H3的27位赖氨酸(H3K27)进行甲基化修饰,进而导致下游靶基因的沉默,在细胞凋亡、细胞周期及细胞分化等重要生物学过程中发挥重要作用。现有研究表明EZH2在卵巢恶性肿瘤中高表达,其表达水平与卵巢癌患者的化疗疗效及预后密切相关。此外,EZH2作为表观遗传修饰因子,影响卵巢癌细胞的增殖、转移及耐药等生物学行为,在肿瘤进展中发挥重要的调控作用。因此,EZH2可能成为卵巢恶性肿瘤有效的治疗新靶点。