Disruption of HDAC4/N-CoR complex by histone deacetylase inhibitors leads to inhibition of IL-2 gene expression.
Previous studies have shown that HDAC inhibitors selectively inhibit IL-2 gene expression, but the mechanism of this inhibition remains to be elucidated. It was recently reported that HDAC4, a component of the nuclear hormone receptor corepressor (N-CoR) complex, associates with the IL-2 promoter via the transcription factor myocyte enhancer factor 2 (MEF2). We therefore focused on the role of HDAC4/N-CoR complex in the transcriptional regulation of IL-2. Four approaches were used to characterize this role and to investigate the relation between the regulatory function of HDAC4/N-CoR complex and HDAC4-enzymatic activity: (i) HDAC4 silencing by RNA interference, (ii) overexpression of N-CoR repression domain 3 (RD3), (iii) overexpression of HDAC4 point mutants, and (iv) treatment with HDAC inhibitors. Here, we report that HDAC4 plays an essential role in IL-2 promoter activation, and that the formation of the HDAC4/N-CoR complex, which is closely related to HDAC4-enzymatic activity, might be involved in HDAC inhibitor-mediated inhibition of IL-2 gene expression. These observations indicate that the selective inhibition of HDAC4 or the interaction of HDAC4 with N-CoR is likely a potential target for the development of novel immunosuppressants.
Matsuoka
Hideaki
H
Pharmacology Research Laboratories, Astellas Pharma Inc., 2-1-6 Kashima, Osaka 532-8514, Japan. hideaki.matsuoka@jp.astellas.com
Fujimura
Takao
T
Hayashi
Masako
M
Matsuda
Kaori
K
Ishii
Yoshinori
Y
Aramori
Ichiro
I
Mutoh
Seitaro
S
D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics; D049668:History, 15th Century; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D056971:Nuclear Receptor Co-Repressor 1; D010456:Peptides, Cyclic / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*
D017931:DNA Primers; D004791:Enzyme Inhibitors; C474179:FR 235222; D056572:Histone Deacetylase Inhibitors; D007376:Interleukin-2; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D010456:Peptides, Cyclic; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D006655:Histone Deacetylases