Co-targeting BET bromodomain BRD4 and RAC1 suppresses growth,stemness and tumorigenesis by disrupting the c-MYC-G9a-FTH1axis and downregulating HDAC1 in molecular subtypes of breast cancer

BET bromodomain BRD4 and RAC1 oncogenes are considered important therapeutic targets for cancer and play key roles in tumorigenesis, survival and metastasis. However, combined inhibition of BRD4-RAC1 signaling pathways in different molecular subtypes of breast cancer including luminal-A, HER-2 positive and triple-negative breast (TNBC) largely remains unknown. Here, we demonstrated a new co-targeting strategy by combined inhibition of BRD4-RAC1 oncogenic signaling in different molecular subtypes of breast cancer in a context-dependent manner. We show that combined treatment of JQ1 (inhibitor of BRD4) and NSC23766 (inhibitor of RAC1) suppresses cell growth, clonogenic potential, cell migration and mammary stem cells expansion and induces autophagy and cellular senescence in molecular subtypes of breast cancer cells. Mechanistically, JQ1/NSC23766 combined treatment disrupts MYC/G9a axis and subsequently enhances FTH1 to exert antitumor effects. Furthermore, combined treatment targets HDAC1/Ac-H3K9 axis, thus suggesting a role of this combination in histone modification and chromatin modeling. C-MYC depletion and co-treatment with vitamin-C sensitizes different molecular subtypes of breast cancer cells to JQ1/NSC23766 combination and further reduces cell growth, cell migration and mammosphere formation. Importantly, co-targeting RAC1-BRD4 suppresses breast tumor growth in vivo using xenograft mouse model. Clinically, RAC1 and BRD4 expression positively correlates in breast cancer patient''s samples and show high expression patterns across different molecular subtypes of breast cancer. Both RAC1 and BRD4 proteins predict poor survival in breast cancer patients. Taken together, our results suggest that combined inhibition of BRD4-RAC1 pathways represents a novel and potential therapeutic approach in different molecular subtypes of breast cancer and highlights the importance of co-targeting RAC1-BRD4 signaling in breast tumorigenesis via disruption of C-MYC/G9a/FTH1 axis and down regulation of HDAC1.     

候选抑瘤基因 BRD7 及家族蛋白的功能研究进展

溴区结构（bromodomain）是近年来发现的广泛分布于多种生物中的一种高度保守的结构域,溴区结构蛋白通过参与信号依赖性的基因转录调控而广泛参与细胞内重要的生命活动．BRD7基因是1999年克隆的一个新的bromodomain基因,GenBank登录号为AF152604或AF152605．eMotif分析表明,BRD7蛋白包含多个磷酸化位点和一个保守bromodomain功能域,Blast显示BRD7蛋白与人的Celtix-1及鼠的bromodomain蛋白BP75具有高度的同源性．利用转基因技术已证实,在鼻咽癌细胞系HNEl中过表达BRD7基因可以抑制其细胞生长和细胞周期G1-S的进程,并部分逆转鼻咽痛细胞HNE1的恶性表型．为了全面地揭示BRD7基因的细胞内生物学功能,深入了解BRD7基因的细胞内整体信息流向,中南大学肿瘤研究所细胞遗传室已从上、中、下游三个不同层面对BRD7基因的功能研究展开了初步的探索．     

候选抑瘤基因 BRD7 及家族蛋白的功能研究进展

溴区结构(bromodomain)是近年来发现的广泛分布于多种生物中的一种高度保守的结构域,溴区结构蛋白通过参与信号依赖性的基因转录调控而广泛参与细胞内重要的生命活动.BRD7基因是1999年克隆的一个新的bromodomain基因,GenBank登录号为AF152604或AF152605.eMotif分析表明,BRD7蛋白包含多个磷酸化位点和一个保守bromodomain功能域,Blast显示BRD7蛋白与人的Celtix-1及鼠的bromodomain蛋白BP75具有高度的同源性.利用转基因技术已证实,在鼻咽癌细胞系HNE1中过表达BRD7基因可以抑制其细胞生长和细胞周期G1-S的进程,并部分逆转鼻咽癌细胞HNE1的恶性表型.为了全面地揭示BRD7基因的细胞内生物学功能,深入了解BRD7基因的细胞内整体信息流向,中南大学肿瘤研究所细胞遗传室已从上、中、下游三个不同层面对BRD7基因的功能研究展开了初步的探索.