Mechanisms of HDAC inhibitor-induced thrombocytopenia
Mechanisms of HDAC inhibitor-induced thrombocytopenia
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DOI：
10.1016/j.ejphar.2007.06.015
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发表时间：
2007-10-01
影响因子：
5
通讯作者：
Mutoh, Seitaro
中科院分区：
文献类型：
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作者：
Matsuoka, Hideaki;Unami, Akira;Mutoh, Seitaro
组蛋白脱乙酰酶抑制剂(HDAC抑制剂)是一类新兴的抗癌药物。为了阐明HDAC抑制剂诱导的血小板减少的机制，我们重点研究了HDAC抑制剂对巨核细胞分化的影响，并对处理前后的人巨核细胞进行了Affymetrix基因芯片分析。在这里，我们报告了GATA-1和10个造血因子(SCL、NF-E2、EKLF、Pleckstrin、凝血酶-R、LMO2、PU.1、Fli-1、AML1和TCF11)在转录上被HDAC抑制剂以相似的模式抑制(R>；0.98)，并且在这些基因的几乎所有的启动子中都发现了GATA-1和10个造血因子(SCL、NF-E2、EKLF、Pleckstrin、凝血酶-R、LMO2、PU.1、Fli-1、AML1和TCF11)。此外，荧光素酶报告分析显示，GATA-1启动子中GATA-1结合位点的突变消除了其对HDAC抑制剂介导的HEL细胞下调的敏感性。此外，该报告还断言，HDAC抑制剂增加了大鼠脾中巨核细胞的数量，并抑制了GATA-1基因的表达。综上所述，这些结果表明，HDAC抑制剂通过降低GATA-1本身的反式激活功能来抑制GATA-1基因的表达，这可能反过来导致巨核细胞成熟延迟，最终导致血小板减少。我们的发现可能有助于我们理解HDAC抑制剂介导的GATA-1转录抑制的分子机制，并降低HDAC抑制剂诱导的血小板减少的风险。(C)2007 Elsevier B.V.保留所有权利。
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. (C) 2007 Elsevier B.V. All rights reserved.