BACKGROUND The overexpression of the MYC gene plays an important role in the occurrence,development and evolution of colorectal cancer(CRC).Bromodomain and extraterminal domain(BET)inhibitors can decrease the function...BACKGROUND The overexpression of the MYC gene plays an important role in the occurrence,development and evolution of colorectal cancer(CRC).Bromodomain and extraterminal domain(BET)inhibitors can decrease the function BET by recognizing acetylated lysine residues,thereby downregulating the expression of MYC.AIM To investigate the inhibitory effect and mechanism of a BET inhibitor on CRC cells.METHODS The effect of the BET inhibitor JAB-8263 on the proliferation of various CRC cell lines was studied by CellTiter-Glo method and colony formation assay.The effect of JAB-8263 on the cell cycle and apoptosis of CRC cells was studied by propidium iodide staining and Annexin V/propidium iodide flow assay,respectively.The effect of JAB-8263 on the expression of c-MYC,p21 and p16 in CRC cells was detected by western blotting assay.The anti-tumor effect of JAB-8263 on CRC cells in vivo and evaluation of the safety of the compound was predicted by constructing a CRC cell animal tumor model.RESULTS JAB-8263 dose-dependently suppressed CRC cell proliferation and colony formation in vitro.The MYC signaling pathway was dose-dependently inhibited by JAB-8263 in human CRC cell lines.JAB-8263 dose-dependently induced cell cycle arrest and apoptosis in the MC38 cell line.SW837 xenograft model was treated with JAB-8263(0.3 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P<0.001).The MC38 syngeneic murine model was treated with JAB-8263(0.2 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P=0.003).CONCLUSION BET could be a potential effective drug target for suppressing CRC growth,and the BET inhibitor JAB-8263 can effectively suppress c-MYC expression and exert anti-tumor activity in CRC models.展开更多
Embryonic stem cells （ESCs） maintain their cellular identity through the systematic regulation of master transcription factors and chromatin remodeling complexes. Recent work has shown that the unusually large-scale...Embryonic stem cells （ESCs） maintain their cellular identity through the systematic regulation of master transcription factors and chromatin remodeling complexes. Recent work has shown that the unusually large-scale enhancers-namely super-enhancers （SEs）, on which BRD4, a member of the bromodomain and extraterminal domain （BET） family is highly enriched-could regulate pluripotency-related transcrip- tion factors. Moreover, inhibition of BRD4 binding on SEs has been shown to induce the differentiation of ESCs. However, the underlying mechanism of BRD4 inhibition-mediated stern cell differentiation remains elusive. Here we show that both mouse and human ESCs lose their capacity for self-renewal upon treat- ment with JQ1, a selective inhibitor of BET family including BRD4, with rapid suppression of pluripotency-associated genes. Notably, a high concentration of JQI could selectively eliminate ESCs via apoptosis, without affecting the functionality of differentiated somatic cells from ESCs, suggesting that inhibition of BET may have a beneficial effect on the development of pluripotent stem cell-based cell therapy.展开更多
溴结构域和超末端结构域(bromodomain and extraterminal domain,Bet)家族是表观基因组的调节因子,也是肿瘤细胞生存所依赖的肿瘤相关基因表达的关键驱动因子。溴结构域蛋白4(bromodomain-containing protein 4,Brd4)是溴域和端外蛋白...溴结构域和超末端结构域(bromodomain and extraterminal domain,Bet)家族是表观基因组的调节因子,也是肿瘤细胞生存所依赖的肿瘤相关基因表达的关键驱动因子。溴结构域蛋白4(bromodomain-containing protein 4,Brd4)是溴域和端外蛋白家族中的一员,通常识别乙酰化组蛋白,并定位于目的基因的启动子或增强子区域,启动并维持肿瘤相关基因的表达。Brd4与多种转录因子调控和染色质修饰密切相关,并参与DNA损伤修复、维持端粒功能,从而维持肿瘤细胞的存活。本文围绕Brd4蛋白的结构、功能及其抑制剂在肿瘤研究中的应用进行综述。展开更多
BET(bromodomain and extraterminal)是一类能解读表观遗传密码的蛋白,通过识别和结合乙酰化的组蛋白或非组蛋白,在调节基因转录中发挥重要的作用。BET抑制剂在肿瘤和炎症等临床前疾病模型中表现出良好的疗效,且已有部分抑制剂进入临床...BET(bromodomain and extraterminal)是一类能解读表观遗传密码的蛋白,通过识别和结合乙酰化的组蛋白或非组蛋白,在调节基因转录中发挥重要的作用。BET抑制剂在肿瘤和炎症等临床前疾病模型中表现出良好的疗效,且已有部分抑制剂进入临床阶段,这表明以BET为治疗靶点的药物研发具有可观前景。本文将对BET蛋白的结构功能、BET抑制剂与疾病治疗以及其作为治疗靶点的分子机制等方面进行阐述。展开更多
基金Supported by the National Natural Science Foundation of China,No.81871317.
文摘BACKGROUND The overexpression of the MYC gene plays an important role in the occurrence,development and evolution of colorectal cancer(CRC).Bromodomain and extraterminal domain(BET)inhibitors can decrease the function BET by recognizing acetylated lysine residues,thereby downregulating the expression of MYC.AIM To investigate the inhibitory effect and mechanism of a BET inhibitor on CRC cells.METHODS The effect of the BET inhibitor JAB-8263 on the proliferation of various CRC cell lines was studied by CellTiter-Glo method and colony formation assay.The effect of JAB-8263 on the cell cycle and apoptosis of CRC cells was studied by propidium iodide staining and Annexin V/propidium iodide flow assay,respectively.The effect of JAB-8263 on the expression of c-MYC,p21 and p16 in CRC cells was detected by western blotting assay.The anti-tumor effect of JAB-8263 on CRC cells in vivo and evaluation of the safety of the compound was predicted by constructing a CRC cell animal tumor model.RESULTS JAB-8263 dose-dependently suppressed CRC cell proliferation and colony formation in vitro.The MYC signaling pathway was dose-dependently inhibited by JAB-8263 in human CRC cell lines.JAB-8263 dose-dependently induced cell cycle arrest and apoptosis in the MC38 cell line.SW837 xenograft model was treated with JAB-8263(0.3 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P<0.001).The MC38 syngeneic murine model was treated with JAB-8263(0.2 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P=0.003).CONCLUSION BET could be a potential effective drug target for suppressing CRC growth,and the BET inhibitor JAB-8263 can effectively suppress c-MYC expression and exert anti-tumor activity in CRC models.
基金supported by the National Research Foundation of Korea(NRF-2016K1A3A1A61006005,NRF-2016R1A2B3011860,NRF-2016R1A5A2012284,and NRF-2017M3C7A1047640)
文摘Embryonic stem cells （ESCs） maintain their cellular identity through the systematic regulation of master transcription factors and chromatin remodeling complexes. Recent work has shown that the unusually large-scale enhancers-namely super-enhancers （SEs）, on which BRD4, a member of the bromodomain and extraterminal domain （BET） family is highly enriched-could regulate pluripotency-related transcrip- tion factors. Moreover, inhibition of BRD4 binding on SEs has been shown to induce the differentiation of ESCs. However, the underlying mechanism of BRD4 inhibition-mediated stern cell differentiation remains elusive. Here we show that both mouse and human ESCs lose their capacity for self-renewal upon treat- ment with JQ1, a selective inhibitor of BET family including BRD4, with rapid suppression of pluripotency-associated genes. Notably, a high concentration of JQI could selectively eliminate ESCs via apoptosis, without affecting the functionality of differentiated somatic cells from ESCs, suggesting that inhibition of BET may have a beneficial effect on the development of pluripotent stem cell-based cell therapy.
文摘溴结构域和超末端结构域(bromodomain and extraterminal domain,Bet)家族是表观基因组的调节因子,也是肿瘤细胞生存所依赖的肿瘤相关基因表达的关键驱动因子。溴结构域蛋白4(bromodomain-containing protein 4,Brd4)是溴域和端外蛋白家族中的一员,通常识别乙酰化组蛋白,并定位于目的基因的启动子或增强子区域,启动并维持肿瘤相关基因的表达。Brd4与多种转录因子调控和染色质修饰密切相关,并参与DNA损伤修复、维持端粒功能,从而维持肿瘤细胞的存活。本文围绕Brd4蛋白的结构、功能及其抑制剂在肿瘤研究中的应用进行综述。
文摘BET(bromodomain and extraterminal)是一类能解读表观遗传密码的蛋白,通过识别和结合乙酰化的组蛋白或非组蛋白,在调节基因转录中发挥重要的作用。BET抑制剂在肿瘤和炎症等临床前疾病模型中表现出良好的疗效,且已有部分抑制剂进入临床阶段,这表明以BET为治疗靶点的药物研发具有可观前景。本文将对BET蛋白的结构功能、BET抑制剂与疾病治疗以及其作为治疗靶点的分子机制等方面进行阐述。
