In recent years,the histone methyltransferase SET domain containing 2(SETD2)has garnered significant attention for its involvement in carcinogenesis.Herein we aim to summarize the research advances regarding SETD2 in ...In recent years,the histone methyltransferase SET domain containing 2(SETD2)has garnered significant attention for its involvement in carcinogenesis.Herein we aim to summarize the research advances regarding SETD2 in tumors,elucidate the role in global epigenetic regulation,highlight potential therapeutic regimens for patients with SETD2 deficiency,and outline future research directions.展开更多
目的分析甲基转移酶SETD2表达改变对人鼻咽癌(NPC)细胞中蛋白表达谱的影响并富集差异信号通路。方法提取SETD2基因敲除细胞株CNE1SETD2-KO和野生型细胞CNE1WT的总蛋白,利用Tandem Mass Tag(TMT)标记蛋白质定量技术和串联质谱分析技术筛...目的分析甲基转移酶SETD2表达改变对人鼻咽癌(NPC)细胞中蛋白表达谱的影响并富集差异信号通路。方法提取SETD2基因敲除细胞株CNE1SETD2-KO和野生型细胞CNE1WT的总蛋白,利用Tandem Mass Tag(TMT)标记蛋白质定量技术和串联质谱分析技术筛选出差异表达蛋白质,应用GO数据库对差异表达蛋白质进行注释和富集,应用KEGG数据库进行差异蛋白质涉及信号通路富集。结果以表达倍数(FC)≥1.2倍且P<0.05为筛选标准,SETD2基因敲除的CNE1细胞鉴别出2049个差异表达蛋白质,其中904个表达上调,1145个表达下调。GO功能注释结果表明,SETD2敲除后在生物过程(细胞过程及调节,细胞运动、代谢过程及细胞组分的生物合成)、分子功能(催化活性及分子结合、转录因子活性)和细胞组分(胞膜、细胞器、大分子复合物)等具有特征性。KEGG信号富集结果表明SETD2敲除主要影响与肿瘤关系密切的信号有MAPK、PI3K-Akt、Ras、Rap1、mTOR、Hippo、HIF-1、Wnt、AMPK、FoxO、ErbB、p53、JAK-STAT等。结论SETD2敲除后显著改变了NPC细胞中蛋白质表达特征并影响多条与肿瘤关系密切的信号通路,研究结果为NPC的发病机制和治疗标靶筛选提供了参考。展开更多
SETD2是哺乳动物中唯一的组蛋白H3K36的特异性三甲基转移酶,它的编码基因位于第三号染色体的3p21.31区域。SETD2蛋白是一个230 k D、含有SET结构域的蛋白,最早是由人造血干细胞分离的,也被认为是与亨廷顿病的发病机制相关。它是生物转...SETD2是哺乳动物中唯一的组蛋白H3K36的特异性三甲基转移酶,它的编码基因位于第三号染色体的3p21.31区域。SETD2蛋白是一个230 k D、含有SET结构域的蛋白,最早是由人造血干细胞分离的,也被认为是与亨廷顿病的发病机制相关。它是生物转录延伸过程中的重要组成部分,能够与RNA聚合酶Ⅱ的最大亚基Rbp1结合,参与基因的转录延伸。SETD2还能通过编码区的去乙酰化抑制转录起始的频率以保证基因转录的高保真度,从而预防肿瘤的发生;同时SETD2也能激活转录因子p53及下游凋亡靶基因发挥抑癌作用。SETD2在DNA修复方面也具有重要作用,它是人错配基因修复和人同源基因修复过程中不可缺少的重要部分。已经有研究表明在多种肿瘤中SETD2均发生了突变,包括肾透明细胞癌、小儿晚期神经胶质瘤、急性T淋巴细胞白血病等,对某些特定肿瘤的分期和预后也有显著影响。本文将介绍SETD2在人体内的多种功能,并对其在肿瘤发生发展中的作用机制进行综述。展开更多
SETD2 is the only enzyme responsible for transcription-coupled histone H3 lysine 36 trimethylation(H3K36me3).Mutations in SETD2 cause human diseases including cancer and developmental defects.In mice,Setd2 is essentia...SETD2 is the only enzyme responsible for transcription-coupled histone H3 lysine 36 trimethylation(H3K36me3).Mutations in SETD2 cause human diseases including cancer and developmental defects.In mice,Setd2 is essential for embryonic vascular remodeling.Given that many epigenetic modifiers have recently been found to possess noncatalytic functions,it is unknown whether the major function(s)of Setd2 is dependent on its catalytic activity or not.Here,we established a site-specific knockin mouse model harboring a cancer patientderived catalytically dead Setd2(Setd2-CD).We found that the essentiality of Setd2 in mouse development is dependent on its methyltransferase activity,as the Setd2 CD/CD and Setd2^(−/−)mice showed similar embryonic lethal phenotypes and largely comparable gene expression patterns.However,compared with Setd2^(−/−),the Setd2 CD/CD mice showed less severe defects in allantois development,and single-cell RNA-seq analysis revealed differentially regulated allantois-specific 5′Hoxa cluster genes in these two models.Collectively,this study clarifies the importance of Setd2 catalytic activity in mouse development and provides a new model for comparative study of previously unrecognized Setd2 functions.展开更多
SETD2 is the main transferase for the trimethylation of histone H3 at lysine 36 (H3K36me3) in mammals. SETD2 plays important role in repairing DNA double strand breaks and maintaining chromatin integrity.1 In renal ca...SETD2 is the main transferase for the trimethylation of histone H3 at lysine 36 (H3K36me3) in mammals. SETD2 plays important role in repairing DNA double strand breaks and maintaining chromatin integrity.1 In renal carcinoma, SETD2 deficiency caused DNA replication fork instability and DNA damage.2 The absence of SETD2 was also reported to have strong tumor-promoting effects in lung adenocarcinomas (LUAD).3 However, the other roles of SETD2 remain poorly understood in LUAD. In this study, we utilized comprehensive omics-data analysis to determine that SETD2 was associated with DNA damage and immune-related signals in LUAD. SETD2 knockdown induced DNA damage and cGAS activation in LUAD cells, and reduced the number of cells at the G1 phase. Moreover, SETD2 deficiency was conducive to mutation burden, immune cell infiltration, and immunotherapy responses. High SETD2 expression was associated with high radiocurability. These findings suggest that SETD2 may be a promising biomarker of therapeutic responses for LUAD patients, and offer novel insights into immunotherapy and radiotherapy.展开更多
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.82073105 and 32370833)the State Key Laboratory of Systems Medicine for Cancer(Grant No.KF2412).
文摘In recent years,the histone methyltransferase SET domain containing 2(SETD2)has garnered significant attention for its involvement in carcinogenesis.Herein we aim to summarize the research advances regarding SETD2 in tumors,elucidate the role in global epigenetic regulation,highlight potential therapeutic regimens for patients with SETD2 deficiency,and outline future research directions.
文摘目的分析甲基转移酶SETD2表达改变对人鼻咽癌(NPC)细胞中蛋白表达谱的影响并富集差异信号通路。方法提取SETD2基因敲除细胞株CNE1SETD2-KO和野生型细胞CNE1WT的总蛋白,利用Tandem Mass Tag(TMT)标记蛋白质定量技术和串联质谱分析技术筛选出差异表达蛋白质,应用GO数据库对差异表达蛋白质进行注释和富集,应用KEGG数据库进行差异蛋白质涉及信号通路富集。结果以表达倍数(FC)≥1.2倍且P<0.05为筛选标准,SETD2基因敲除的CNE1细胞鉴别出2049个差异表达蛋白质,其中904个表达上调,1145个表达下调。GO功能注释结果表明,SETD2敲除后在生物过程(细胞过程及调节,细胞运动、代谢过程及细胞组分的生物合成)、分子功能(催化活性及分子结合、转录因子活性)和细胞组分(胞膜、细胞器、大分子复合物)等具有特征性。KEGG信号富集结果表明SETD2敲除主要影响与肿瘤关系密切的信号有MAPK、PI3K-Akt、Ras、Rap1、mTOR、Hippo、HIF-1、Wnt、AMPK、FoxO、ErbB、p53、JAK-STAT等。结论SETD2敲除后显著改变了NPC细胞中蛋白质表达特征并影响多条与肿瘤关系密切的信号通路,研究结果为NPC的发病机制和治疗标靶筛选提供了参考。
文摘SETD2是哺乳动物中唯一的组蛋白H3K36的特异性三甲基转移酶,它的编码基因位于第三号染色体的3p21.31区域。SETD2蛋白是一个230 k D、含有SET结构域的蛋白,最早是由人造血干细胞分离的,也被认为是与亨廷顿病的发病机制相关。它是生物转录延伸过程中的重要组成部分,能够与RNA聚合酶Ⅱ的最大亚基Rbp1结合,参与基因的转录延伸。SETD2还能通过编码区的去乙酰化抑制转录起始的频率以保证基因转录的高保真度,从而预防肿瘤的发生;同时SETD2也能激活转录因子p53及下游凋亡靶基因发挥抑癌作用。SETD2在DNA修复方面也具有重要作用,它是人错配基因修复和人同源基因修复过程中不可缺少的重要部分。已经有研究表明在多种肿瘤中SETD2均发生了突变,包括肾透明细胞癌、小儿晚期神经胶质瘤、急性T淋巴细胞白血病等,对某些特定肿瘤的分期和预后也有显著影响。本文将介绍SETD2在人体内的多种功能,并对其在肿瘤发生发展中的作用机制进行综述。
基金supported by the Center for High Performance Computing at Shanghai Jiao Tong Universitysupported by the National Key R&D Plan of China(No.2018YFA0107802 to Xiaojian Sun,Nos.2018YFA0107200 and 2018YFA0800203 to Lan Wang)+3 种基金the National Natural Science Foundation of China General Program(Nos.81970150 and 82170156 to Lan Wang)Shanghai“Science and Technology Innovation Action Plan”Excellent Academic/Technical Leader Program(Youth)(No.21XD1424500 to Lan Wang)Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(No.2019CXJQ01 to Saijuan Chen and Xiaojian Sun)Samuel Waxman Cancer Research Foundation,and the Shanghai Guangci Translational Medical Research Development Foundation.
文摘SETD2 is the only enzyme responsible for transcription-coupled histone H3 lysine 36 trimethylation(H3K36me3).Mutations in SETD2 cause human diseases including cancer and developmental defects.In mice,Setd2 is essential for embryonic vascular remodeling.Given that many epigenetic modifiers have recently been found to possess noncatalytic functions,it is unknown whether the major function(s)of Setd2 is dependent on its catalytic activity or not.Here,we established a site-specific knockin mouse model harboring a cancer patientderived catalytically dead Setd2(Setd2-CD).We found that the essentiality of Setd2 in mouse development is dependent on its methyltransferase activity,as the Setd2 CD/CD and Setd2^(−/−)mice showed similar embryonic lethal phenotypes and largely comparable gene expression patterns.However,compared with Setd2^(−/−),the Setd2 CD/CD mice showed less severe defects in allantois development,and single-cell RNA-seq analysis revealed differentially regulated allantois-specific 5′Hoxa cluster genes in these two models.Collectively,this study clarifies the importance of Setd2 catalytic activity in mouse development and provides a new model for comparative study of previously unrecognized Setd2 functions.
基金supported by National Natural Science Foundation,China(No.81972852,81800429)Key Research&Development Project of Hubei Province,China(No.2020BCA069)+3 种基金Nature Science Foundation of Hubei Province,China(No.2020CFB612)Young and Middle-Aged Medical Backbone Talents of Wuhan,China(No.WHQG201902)Application Foundation Frontier Project of Wuhan,China(No.2020020601012221)Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University,China(No.ZNJC201922,ZNJC202007).
文摘SETD2 is the main transferase for the trimethylation of histone H3 at lysine 36 (H3K36me3) in mammals. SETD2 plays important role in repairing DNA double strand breaks and maintaining chromatin integrity.1 In renal carcinoma, SETD2 deficiency caused DNA replication fork instability and DNA damage.2 The absence of SETD2 was also reported to have strong tumor-promoting effects in lung adenocarcinomas (LUAD).3 However, the other roles of SETD2 remain poorly understood in LUAD. In this study, we utilized comprehensive omics-data analysis to determine that SETD2 was associated with DNA damage and immune-related signals in LUAD. SETD2 knockdown induced DNA damage and cGAS activation in LUAD cells, and reduced the number of cells at the G1 phase. Moreover, SETD2 deficiency was conducive to mutation burden, immune cell infiltration, and immunotherapy responses. High SETD2 expression was associated with high radiocurability. These findings suggest that SETD2 may be a promising biomarker of therapeutic responses for LUAD patients, and offer novel insights into immunotherapy and radiotherapy.
