表观遗传包括DNA甲基化、组蛋白修饰、染色体重塑和非编码RNA调控等,主要通过调控基因转录和翻译过程影响基因的表达。目前认为在多数肿瘤中存在异常的表观遗传修饰,而参与肿瘤的形成、进展以及复发和转移。了解并使用这些标记来完善肿...表观遗传包括DNA甲基化、组蛋白修饰、染色体重塑和非编码RNA调控等,主要通过调控基因转录和翻译过程影响基因的表达。目前认为在多数肿瘤中存在异常的表观遗传修饰,而参与肿瘤的形成、进展以及复发和转移。了解并使用这些标记来完善肿瘤诊断标准、指导治疗方案的实施及更有效预后评估变得更重要。核受体结合SET结构域蛋白2(nuclear SET domain-containing protein 2,NSD2)是一种组蛋白甲基化转移酶(the histone methyltransferase,HMT),通过催化组蛋白H3赖氨酸残基甲基化,影响基因表达,产生生物学效应。越来越多的研究证实NSD2与B细胞淋巴的发生、发展密切相关,NSD2可能成为肿瘤治疗的新靶点。该文将NSD2在B淋巴瘤中的研究进展作一综述。展开更多
Nuclear Receptor-binding SET Domain 2 (NSD2) is a SET domain-containing protein lysine methyltransferase (PKMT) implicated in a lot of human diseases. Its haploinsufficiency is implicated in the developmental disorder...Nuclear Receptor-binding SET Domain 2 (NSD2) is a SET domain-containing protein lysine methyltransferase (PKMT) implicated in a lot of human diseases. Its haploinsufficiency is implicated in the developmental disorder Wolf Hirschhorn syndrome (WHS), which is characterized by growth and mental retardation, congenital heart defects, etc. Moreover, it is over-expressed in a large number of tumors, including malignant melanoma. However, the underlying mechanisms of its deregulation in most tumors are still not unclear.展开更多
组蛋白的修饰通过调节染色质结构的疏密程度从而影响基因转录等与DNA有关的生物学功能。NSD蛋白家族(nuclear receptor binding SET domain proteins)(包括NSD1-3)是一组与肿瘤发生相关的组蛋白甲基化转移酶,其中又以NSD2与肿瘤的关系...组蛋白的修饰通过调节染色质结构的疏密程度从而影响基因转录等与DNA有关的生物学功能。NSD蛋白家族(nuclear receptor binding SET domain proteins)(包括NSD1-3)是一组与肿瘤发生相关的组蛋白甲基化转移酶,其中又以NSD2与肿瘤的关系最为密切。近年来的研究发现,NSD2在多发性骨髓瘤、神经母细胞瘤及肝癌等多种肿瘤中高表达,并且相关病人的预后较差。NSD2呈现多种原癌基因的特征:NSD2高表达促进细胞增殖、克隆形成、侵袭能力增强以及肿瘤移植物的生长等。然而,NSD1与NSD3虽然可以与核孔蛋白98 k Da(nucleoporin 98 k Da,NUP98)形成融合蛋白,在部分急性髓性白血病中有致瘤作用,但是它们本身却具有抑癌基因的特点。该文就NSD蛋白家族的最新研究进展作一综述,阐述了NSD蛋白家族在肿瘤发生发展中的作用及潜在的应用前景。展开更多
Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance.However,their interplays are poorly understood.We report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regu...Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance.However,their interplays are poorly understood.We report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regulator),an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2(nuclear receptor binding SET domain protein 2),is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark.Mechanistically,TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2,H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new(NSD2)and established(NQO1/2,PRDX1 and GSTM4)targets of NRF2,independent of its enzymatic activity.Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis.In addition,nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival.These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.展开更多
文摘表观遗传包括DNA甲基化、组蛋白修饰、染色体重塑和非编码RNA调控等,主要通过调控基因转录和翻译过程影响基因的表达。目前认为在多数肿瘤中存在异常的表观遗传修饰,而参与肿瘤的形成、进展以及复发和转移。了解并使用这些标记来完善肿瘤诊断标准、指导治疗方案的实施及更有效预后评估变得更重要。核受体结合SET结构域蛋白2(nuclear SET domain-containing protein 2,NSD2)是一种组蛋白甲基化转移酶(the histone methyltransferase,HMT),通过催化组蛋白H3赖氨酸残基甲基化,影响基因表达,产生生物学效应。越来越多的研究证实NSD2与B细胞淋巴的发生、发展密切相关,NSD2可能成为肿瘤治疗的新靶点。该文将NSD2在B淋巴瘤中的研究进展作一综述。
文摘Nuclear Receptor-binding SET Domain 2 (NSD2) is a SET domain-containing protein lysine methyltransferase (PKMT) implicated in a lot of human diseases. Its haploinsufficiency is implicated in the developmental disorder Wolf Hirschhorn syndrome (WHS), which is characterized by growth and mental retardation, congenital heart defects, etc. Moreover, it is over-expressed in a large number of tumors, including malignant melanoma. However, the underlying mechanisms of its deregulation in most tumors are still not unclear.
文摘组蛋白的修饰通过调节染色质结构的疏密程度从而影响基因转录等与DNA有关的生物学功能。NSD蛋白家族(nuclear receptor binding SET domain proteins)(包括NSD1-3)是一组与肿瘤发生相关的组蛋白甲基化转移酶,其中又以NSD2与肿瘤的关系最为密切。近年来的研究发现,NSD2在多发性骨髓瘤、神经母细胞瘤及肝癌等多种肿瘤中高表达,并且相关病人的预后较差。NSD2呈现多种原癌基因的特征:NSD2高表达促进细胞增殖、克隆形成、侵袭能力增强以及肿瘤移植物的生长等。然而,NSD1与NSD3虽然可以与核孔蛋白98 k Da(nucleoporin 98 k Da,NUP98)形成融合蛋白,在部分急性髓性白血病中有致瘤作用,但是它们本身却具有抑癌基因的特点。该文就NSD蛋白家族的最新研究进展作一综述,阐述了NSD蛋白家族在肿瘤发生发展中的作用及潜在的应用前景。
基金This work was supported by the National Natural Science Foundation of China(81872891)the Guangdong Natural Science Funds for Distinguished Young Scholar(No.2019B151502016,China)+4 种基金Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China)National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004,China)the Fundamental Research Funds for the Central Universities(No.19ykzd23,China)The Manitoba Breast Tumor Bank,a member of the Canadian Tissue Repository Network,was funded in part by the Cancer Care Manitoba Foundation(CCMF,Canada)previously the Canadian Institutes of Health Research(CIHR,PRG80155,Canada).
文摘Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance.However,their interplays are poorly understood.We report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regulator),an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2(nuclear receptor binding SET domain protein 2),is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark.Mechanistically,TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2,H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new(NSD2)and established(NQO1/2,PRDX1 and GSTM4)targets of NRF2,independent of its enzymatic activity.Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis.In addition,nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival.These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.
