Mechanisms of HDAC inhibitor-induced thrombocytopenia.
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.
Matsuoka
Hideaki
H
Pharmacology Research Laboratories, Astellas Pharma Inc., 2 1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. hideaki.matsuoka@us.astellas.com
Unami
Akira
A
Fujimura
Takao
T
Noto
Takahisa
T
Takata
Yoko
Y
Yoshizawa
Katsuhiko
K
Mori
Hiroaki
H
Aramori
Ichiro
I
Mutoh
Seitaro
S
D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001772:Blood Cell Count; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D017930:Genes, Reporter; D006410:Hematopoiesis / Q000187:drug effects* / Q000235:genetics; D016298:Hematopoietic Cell Growth Factors / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010456:Peptides, Cyclic / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C474179:FR 235222; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494690:Gata1 protein, rat; D016298:Hematopoietic Cell Growth Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010456:Peptides, Cyclic; C100692:oxamflatin; D008156:Luciferases; D006655:Histone Deacetylases