交易激励
组蛋白脱乙酰基酶
组蛋白脱乙酰酶抑制剂
分子生物学
HDAC1型
发起人
巨核细胞
化学
生物
造血
心理压抑
基因表达
基因
细胞生物学
癌症研究
组蛋白
生物化学
干细胞
作者
Hiroaki Matsuoka,Akira Unami,Takao Fujimura,Takahisa Noto,Yoko Takata,Katsuhiko Yoshizawa,Hajime Mori,Ichiro Aramori,Seitaro Mutoh
标识
DOI:10.1016/j.ejphar.2007.06.015
摘要
Histone deacetylase inhibitors (HDAC inhibitors) are an emerging class of anticancer agents. To elucidate the mechanism of HDAC inhibitor-induced thrombocytopenia, we focused on the effects of HDAC inhibitors on megakaryocyte differentiation and performed Affymetrix GeneChip analysis of human megakaryocytic HEL cells treated with or without HDAC inhibitors. Here, we report that GATA-1 and 10 haematopoietic factors (SCL, NF-E2, EKLF, Pleckstrin, Thrombin-R, LMO2, PU.1, Fli-1, AML1, and TCF11) are transcriptionally repressed by HDAC inhibitors in a similar pattern (R > 0.98), and putative GATA-1-binding sites are found in almost all promoters of these genes. In addition, luciferase reporter assays reveal that mutations of GATA-1-binding sites in the GATA-1 promoter abolish its sensitivity to HDAC inhibitor-mediated down-regulation in HEL cells. Further, this report also asserts that HDAC inhibitor increases megakaryocyte counts and inhibits GATA-1 gene expression in rat spleen. Together, these results suggest that HDAC inhibitors inhibit GATA-1 gene expression by decreasing the transactivation function of GATA-1 itself, and that this may in turn lead to a delay in megakaryocyte maturation and finally cause thrombocytopenia. Our findings may help our understanding of the molecular mechanism of HDAC inhibitor-mediated GATA-1 transcriptional repression and to reduce the risk of HDAC inhibitor-induced thrombocytopenia.
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