TY - JOUR
T1 - Requirement of histone deacetylase activity for signaling by STAT1
AU - Klampfer, Lidija
AU - Huang, Jie
AU - Swaby, Laurie Anne
AU - Augenlicht, Leonard
PY - 2004/7/16
Y1 - 2004/7/16
N2 - STAT1 is a transcription factor that plays a crucial role in signaling by interferons (IFNs). In this study we demonstrated that inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNγ-induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1-dependent gene activation Furthermore, we showed that silencing of HDAC1, HDAC2, and HDAC3 through RNA interference markedly decreased IFNγ-driven gene activation and that overexpression of HDAC1, HDAC2, and HDAC3 enhanced STAT1-dependent transcriptional activity. Our data therefore established the essential role of deacetylase activity in STAT1 signaling. Induction of IRF-1 by IFNγ requires functional STAT1 signaling and was abrogated by butyrate, trichostatin A, suberoylanilide hydroxamic acid, and STAT1 small interfering RNA. In contrast, silencing of STAT1 did not interfere with IFNγ-induced expression of STAT2 and caspase-7, and HDAC inhibitors did not preclude IFNγ-induced expression of STAT1, STAT2, and caspase-7, suggesting that HDAC inhibitors impede the expression of IFNγ target genes whose expression depends on STAT1 but do not interfere with STAT1-independent signaling by IFNγ. Finally, we showed that inhibitors of deacetylase activity sensitized colon cancer cells to IFNγ-induced apoptosis through cooperative negative regulation of Bcl-x expression, demonstrating that interruption of the balance between STAT1-dependent and STAT1-independent signaling significantly alters the biological activity of IFNγ.
AB - STAT1 is a transcription factor that plays a crucial role in signaling by interferons (IFNs). In this study we demonstrated that inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNγ-induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1-dependent gene activation Furthermore, we showed that silencing of HDAC1, HDAC2, and HDAC3 through RNA interference markedly decreased IFNγ-driven gene activation and that overexpression of HDAC1, HDAC2, and HDAC3 enhanced STAT1-dependent transcriptional activity. Our data therefore established the essential role of deacetylase activity in STAT1 signaling. Induction of IRF-1 by IFNγ requires functional STAT1 signaling and was abrogated by butyrate, trichostatin A, suberoylanilide hydroxamic acid, and STAT1 small interfering RNA. In contrast, silencing of STAT1 did not interfere with IFNγ-induced expression of STAT2 and caspase-7, and HDAC inhibitors did not preclude IFNγ-induced expression of STAT1, STAT2, and caspase-7, suggesting that HDAC inhibitors impede the expression of IFNγ target genes whose expression depends on STAT1 but do not interfere with STAT1-independent signaling by IFNγ. Finally, we showed that inhibitors of deacetylase activity sensitized colon cancer cells to IFNγ-induced apoptosis through cooperative negative regulation of Bcl-x expression, demonstrating that interruption of the balance between STAT1-dependent and STAT1-independent signaling significantly alters the biological activity of IFNγ.
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U2 - 10.1074/jbc.M401359200
DO - 10.1074/jbc.M401359200
M3 - Article
C2 - 15123634
AN - SCOPUS:3142721913
SN - 0021-9258
VL - 279
SP - 30358
EP - 30368
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 29
ER -