Lysine-specific demethylase 4 A(KDM4A,also named JMJD2A,KIA0677,or JHDM3A)is a demethylase that can remove methyl groups from histones H3K9me2/3,H3K36me2/3,and H1.4K26me2/me3.Accumulating evidence suggests that KDM4A ...Lysine-specific demethylase 4 A(KDM4A,also named JMJD2A,KIA0677,or JHDM3A)is a demethylase that can remove methyl groups from histones H3K9me2/3,H3K36me2/3,and H1.4K26me2/me3.Accumulating evidence suggests that KDM4A is not only involved in body homeostasis(such as cell proliferation,migration and differentiation,and tissue development)but also associated with multiple human diseases,especially cancers.Recently,an increasing number of studies have shown that pharmacological inhibition of KDM4A significantly attenuates tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia.Although there are several reviews on the roles of the KDM4 subfamily in cancer development and therapy,all of them only briefly introduce the roles of KDM4A in cancer without systematically summarizing the specific mechanisms of KDM4A in various physiological and pathological processes,especially in tumorigenesis,which greatly limits advances in the understanding of the roles of KDM4A in a variety of cancers,discovering targeted selective KDM4A inhibitors,and exploring the adaptive profiles of KDM4A antagonists.Herein,we present the structure and functions of KDM4A,simply outline the functions of KDM4A in homeostasis and non-cancer diseases,summarize the role of KDM4A and its distinct target genes in the development of a variety of cancers,systematically classify KDM4A inhibitors,summarize the difficulties encountered in the research of KDM4A and the discovery of related drugs,and provide the corresponding solutions,which would contribute to understanding the recent research trends on KDM4A and advancing the progression of KDM4A as a drug target in cancer therapy.展开更多
Objective Gastrointestinal stromal tumors(GISTs)can rapidly proliferate through angiogenesis.Previous studies indicated the potential influence of microRNA on the progression of tumor immature angiogenesis.This study ...Objective Gastrointestinal stromal tumors(GISTs)can rapidly proliferate through angiogenesis.Previous studies indicated the potential influence of microRNA on the progression of tumor immature angiogenesis.This study aimed to explore the specific mechanism by which microRNA-409-5p(miR-409-5p)contributes to GIST.Methods To identify genes potentially involved in the development and progression of GIST,the differences of miR-409-5p between tumors and adjacent tissues were first analyzed.Following this analysis,target genes were predicted.To further investigate the function of miRNA in GIST cells,two GIST cell lines(GIST-T1 and GIST882)were transfected with lentiviruses that stably expressed miR-409-5p and scrambled miRNA(negative control).Later,the cells were subjected to Western blotting and ELSA to determine any differences in angiogenesis-related genes.Results In GISTs,there was a decrease in the expression levels of miR-409-5p compared to the adjacent tissues.It was observed that the upregulation of miR-409-5p in GIST cell lines effectively inhibited the proteins hypoxia-inducible transcription factor 1β(HIF1β)and vascular endothelial growth factor A(VEGF-A).Further investigations revealed that miR-409-5p acted as an inhibitor of angiogenesis by binding to the 3′-UTR of Lysine-specific demethylase 4D(KDM4D)mRNA.Moreover,the combination of miR-409-5p with imatinib enhanced its inhibitory effect on angiogenesis.Conclusion This study demonstrated that the miRNA-409-5p/KDM4D/HIF1β/VEGF-A signaling pathway could serve as a novel target for the development of therapeutic strategies for the treatment of imatinib-resistance in GIST patients.展开更多
基金supported by the National Natural Science Foundation of China(No.31972821)the General Scientific Research Project of Education of Zhejiang Province,China(No.422204123)the Starting Research Fund of Ningbo University,Zhejiang,China(No.421912073).
文摘Lysine-specific demethylase 4 A(KDM4A,also named JMJD2A,KIA0677,or JHDM3A)is a demethylase that can remove methyl groups from histones H3K9me2/3,H3K36me2/3,and H1.4K26me2/me3.Accumulating evidence suggests that KDM4A is not only involved in body homeostasis(such as cell proliferation,migration and differentiation,and tissue development)but also associated with multiple human diseases,especially cancers.Recently,an increasing number of studies have shown that pharmacological inhibition of KDM4A significantly attenuates tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia.Although there are several reviews on the roles of the KDM4 subfamily in cancer development and therapy,all of them only briefly introduce the roles of KDM4A in cancer without systematically summarizing the specific mechanisms of KDM4A in various physiological and pathological processes,especially in tumorigenesis,which greatly limits advances in the understanding of the roles of KDM4A in a variety of cancers,discovering targeted selective KDM4A inhibitors,and exploring the adaptive profiles of KDM4A antagonists.Herein,we present the structure and functions of KDM4A,simply outline the functions of KDM4A in homeostasis and non-cancer diseases,summarize the role of KDM4A and its distinct target genes in the development of a variety of cancers,systematically classify KDM4A inhibitors,summarize the difficulties encountered in the research of KDM4A and the discovery of related drugs,and provide the corresponding solutions,which would contribute to understanding the recent research trends on KDM4A and advancing the progression of KDM4A as a drug target in cancer therapy.
基金supported by the National Natural Science Foundation of China(No.81372323 and No.81802426).
文摘Objective Gastrointestinal stromal tumors(GISTs)can rapidly proliferate through angiogenesis.Previous studies indicated the potential influence of microRNA on the progression of tumor immature angiogenesis.This study aimed to explore the specific mechanism by which microRNA-409-5p(miR-409-5p)contributes to GIST.Methods To identify genes potentially involved in the development and progression of GIST,the differences of miR-409-5p between tumors and adjacent tissues were first analyzed.Following this analysis,target genes were predicted.To further investigate the function of miRNA in GIST cells,two GIST cell lines(GIST-T1 and GIST882)were transfected with lentiviruses that stably expressed miR-409-5p and scrambled miRNA(negative control).Later,the cells were subjected to Western blotting and ELSA to determine any differences in angiogenesis-related genes.Results In GISTs,there was a decrease in the expression levels of miR-409-5p compared to the adjacent tissues.It was observed that the upregulation of miR-409-5p in GIST cell lines effectively inhibited the proteins hypoxia-inducible transcription factor 1β(HIF1β)and vascular endothelial growth factor A(VEGF-A).Further investigations revealed that miR-409-5p acted as an inhibitor of angiogenesis by binding to the 3′-UTR of Lysine-specific demethylase 4D(KDM4D)mRNA.Moreover,the combination of miR-409-5p with imatinib enhanced its inhibitory effect on angiogenesis.Conclusion This study demonstrated that the miRNA-409-5p/KDM4D/HIF1β/VEGF-A signaling pathway could serve as a novel target for the development of therapeutic strategies for the treatment of imatinib-resistance in GIST patients.
