去甲基化酶FBXL10通过抑制FOXC1促进乳腺癌增殖
摘要
组蛋白去甲基化酶FBXL10(F-box and leucine-rich repeat protein 10)是最大的组蛋白去甲基化酶亚家族JmjC蛋白家族的成员之一,编码它的基因定位于12q24.31,具有特异性的H3K4me3和H3K36me2/1去甲基化酶活性。FBXL10又名JHDM1B(Jmjc domian-containing histone demethylase 1B)、KDM2B(lysine (K)-specific demethylase 2B)、Ndy-1(Not dead yet-1),FBXL10蛋白具有JmjC去甲基化酶活性结构域, CXXC DNA结合结构域, PHD植物同源结构域, proline-rich脯氨酸富集结构域, F-box结构域和leucine-rich repeat结构域。关于FBXL10在癌症方面的功能研究颇有争议,根据细胞背景的不同,可分为抑癌和致癌两方面,已有报道FBXL10在人类淋巴瘤和乳腺癌中有高表达。
转录因子FOXC1是Forkhead box(Fox)家族中的亚家族FOXC的成员之一, FOXC1蛋白含有转录调节区、DNA结合区和一些其他的结构。我们的实验发现FBXL10与FOXC1在两种转移能力不同的乳腺癌细胞系MCF-7和MDA-MB-231中的表达水平呈现明显负相关,进一步分别过表达和干涉实验证实FBXL10能够调控FOXC1基因的转录。本实验室此前的研究表明,FOXC1在乳腺癌细胞系中的外源表达能够抑制乳腺癌细胞的增殖,PcG家族蛋白EZH2能够通过影响FOXC1基因启动子处组蛋白乙酰化和H3K27的三甲基化来抑制FOXC1,而组蛋白去甲基化酶FBXL10在乳腺癌中的功能以及此功能的实现是否与FOXC1有关仍未见报道。
本论文旨在研究组蛋白去甲基化酶FBXL10对乳腺癌细胞增殖的影响及其功能的实现是否通过FOXC1起作用。MTT结果显示,外源过表达去甲基化酶FBXL10能明显促进乳腺癌细胞MCF7的增殖。荧光素酶报告基因、反转录PCR(RT-PCR)和western bloting结果表明,FBXL10可明显抑制FOXC1的表达水平。
本项研究初步探讨了FBXL10在乳腺癌增殖方面的功能,确定了FOXC1为FBXL10又一个全新的靶基因,为深入研究FBXL10基因的功能及其转录调控机制奠定了基础,同时也为进一步揭示FBXL10的生物学功能提供了线索。
FBXL10 gene is a member of the largest histone demethylase Jmjc subfamily,and it is mapped to chromosome 12q24.31,has H3K4me3 and H3K36me2/1-specific demethylase activity.FBXL10 also known as JHDM1B(Jmjc domian-containing histone demethylase 1B)、KDM2B(lysine (K)-specific demethylase 2B)、Ndy-1(Not dead yet-1)。FBXL10 protein has a conserved Jmjc demethylase active domain,CXXC DNA-bingding domain,PHD domain,proline-rich domain,F-box domain and leuine-rich repeat domain.According to the different context of the cells,there is controversy about the function of the FBXL10 on the cancer progression,and it is known that FBXL10 overexpressed in human lymphomas and mammary adenocarcinomas.
Transcription factor FOXC1 is a member of the Forkhead box(FOX) family,possess a transactivation domain,a DNA-bingding domain and some other domains.We discovererd that the expression of FBXL10 gene was negatively correlated to the FOXC1 between two different breast cancer cell lines MCF-7 and MDA-MB-231,and FBXL10 could transcriptionaly regulate the expression of FOXC1 gene by overexpress and RNAi experiment.The research in my lab discovered that overexpression of FOXC1 inhibited proliferation,and EZH2 could represss FOXC1 gene by impacting its histone H3K27 tri-methylation and acetylation modifications.However,it is unreported that the function of histone demethylase FBXL10 in the breast cancer and if the process is related to FOXC1.
The aim of our study was to clarify the function of the histone demethylase FBXL10 on the proliferation and if the function is related to FOXC1.Through MTT,we found that overexpression of FBXL10 could promote proliferation of MCF-7 and by DLR,Reverse Transcription PCR and western blot assays,we found that FBXL10 inhibited FOXC1 expression.
The data presented in this thesis demonstrated the function of FBXL10 to the proliferation of breast cancer cells,and FOXC1 is a new target of FBXL10 protein.The study lays the foundation for the research of the function FBXL10 protein and its transcription regulation mechanism,meanwhile it provides the clues for the biological function of FBXL10.
转录因子FOXC1是Forkhead box(Fox)家族中的亚家族FOXC的成员之一, FOXC1蛋白含有转录调节区、DNA结合区和一些其他的结构。我们的实验发现FBXL10与FOXC1在两种转移能力不同的乳腺癌细胞系MCF-7和MDA-MB-231中的表达水平呈现明显负相关,进一步分别过表达和干涉实验证实FBXL10能够调控FOXC1基因的转录。本实验室此前的研究表明,FOXC1在乳腺癌细胞系中的外源表达能够抑制乳腺癌细胞的增殖,PcG家族蛋白EZH2能够通过影响FOXC1基因启动子处组蛋白乙酰化和H3K27的三甲基化来抑制FOXC1,而组蛋白去甲基化酶FBXL10在乳腺癌中的功能以及此功能的实现是否与FOXC1有关仍未见报道。
本论文旨在研究组蛋白去甲基化酶FBXL10对乳腺癌细胞增殖的影响及其功能的实现是否通过FOXC1起作用。MTT结果显示,外源过表达去甲基化酶FBXL10能明显促进乳腺癌细胞MCF7的增殖。荧光素酶报告基因、反转录PCR(RT-PCR)和western bloting结果表明,FBXL10可明显抑制FOXC1的表达水平。
本项研究初步探讨了FBXL10在乳腺癌增殖方面的功能,确定了FOXC1为FBXL10又一个全新的靶基因,为深入研究FBXL10基因的功能及其转录调控机制奠定了基础,同时也为进一步揭示FBXL10的生物学功能提供了线索。
FBXL10 gene is a member of the largest histone demethylase Jmjc subfamily,and it is mapped to chromosome 12q24.31,has H3K4me3 and H3K36me2/1-specific demethylase activity.FBXL10 also known as JHDM1B(Jmjc domian-containing histone demethylase 1B)、KDM2B(lysine (K)-specific demethylase 2B)、Ndy-1(Not dead yet-1)。FBXL10 protein has a conserved Jmjc demethylase active domain,CXXC DNA-bingding domain,PHD domain,proline-rich domain,F-box domain and leuine-rich repeat domain.According to the different context of the cells,there is controversy about the function of the FBXL10 on the cancer progression,and it is known that FBXL10 overexpressed in human lymphomas and mammary adenocarcinomas.
Transcription factor FOXC1 is a member of the Forkhead box(FOX) family,possess a transactivation domain,a DNA-bingding domain and some other domains.We discovererd that the expression of FBXL10 gene was negatively correlated to the FOXC1 between two different breast cancer cell lines MCF-7 and MDA-MB-231,and FBXL10 could transcriptionaly regulate the expression of FOXC1 gene by overexpress and RNAi experiment.The research in my lab discovered that overexpression of FOXC1 inhibited proliferation,and EZH2 could represss FOXC1 gene by impacting its histone H3K27 tri-methylation and acetylation modifications.However,it is unreported that the function of histone demethylase FBXL10 in the breast cancer and if the process is related to FOXC1.
The aim of our study was to clarify the function of the histone demethylase FBXL10 on the proliferation and if the function is related to FOXC1.Through MTT,we found that overexpression of FBXL10 could promote proliferation of MCF-7 and by DLR,Reverse Transcription PCR and western blot assays,we found that FBXL10 inhibited FOXC1 expression.
The data presented in this thesis demonstrated the function of FBXL10 to the proliferation of breast cancer cells,and FOXC1 is a new target of FBXL10 protein.The study lays the foundation for the research of the function FBXL10 protein and its transcription regulation mechanism,meanwhile it provides the clues for the biological function of FBXL10.
引文
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