Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2004, PMID: 15123634

Requirement of histone deacetylase activity for signaling by STAT1.

Klampfer, Lidija; Huang, Jie; Swaby, Laurie-Anne; Augenlicht, Leonard

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 IFNgamma-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 IFNgamma-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 IFNgamma 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 IFNgamma-induced expression of STAT2 and caspase-7, and HDAC inhibitors did not preclude IFNgamma-induced expression of STAT1, STAT2, and caspase-7, suggesting that HDAC inhibitors impede the expression of IFNgamma target genes whose expression depends on STAT1 but do not interfere with STAT1-independent signaling by IFNgamma. Finally, we showed that inhibitors of deacetylase activity sensitized colon cancer cells to IFNgamma-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 IFNgamma.

Diseases/Pathways annotated by Medline MESH: Inflammation
Document information provided by NCBI PubMed

Text Mining Data

STAT1 → histone deacetylase (HDAC): " In this study we demonstrated that inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNgamma induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1 dependent gene activation "

STAT1 → IFNgamma: " In this study we demonstrated that inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNgamma induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1 dependent gene activation "

JAK1 → histone deacetylase (HDAC): " In this study we demonstrated that inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNgamma induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1 dependent gene activation "

JAK1 → IFNgamma: " In this study we demonstrated that inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNgamma induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1 dependent gene activation "

STAT1 → IFNgamma: " Induction of IRF-1 by IFNgamma requires functional STAT1 signaling and was abrogated by butyrate, trichostatin A, suberoylanilide hydroxamic acid, and STAT1 small interfering RNA "

STAT1 → IRF-1: " Induction of IRF-1 by IFNgamma requires functional STAT1 signaling and was abrogated by butyrate, trichostatin A, suberoylanilide hydroxamic acid, and STAT1 small interfering RNA "

IRF-1 → IFNgamma: " Induction of IRF-1 by IFNgamma requires functional STAT1 signaling and was abrogated by butyrate, trichostatin A, suberoylanilide hydroxamic acid, and STAT1 small interfering RNA "

STAT1 → IFNgamma: " In contrast, silencing of STAT1 did not interfere with IFNgamma induced expression of STAT2 and caspase-7, and HDAC inhibitors did not preclude IFNgamma induced expression of STAT1 , STAT2, and caspase-7, suggesting that HDAC inhibitors impede the expression of IFNgamma target genes whose expression depends on STAT1 but do not interfere with STAT1 independent signaling by IFNgamma "

STAT2 → IFNgamma: " In contrast, silencing of STAT1 did not interfere with IFNgamma induced expression of STAT2 and caspase-7, and HDAC inhibitors did not preclude IFNgamma induced expression of STAT1, STAT2 , and caspase-7, suggesting that HDAC inhibitors impede the expression of IFNgamma target genes whose expression depends on STAT1 but do not interfere with STAT1 independent signaling by IFNgamma "

caspase-7 → IFNgamma: " In contrast, silencing of STAT1 did not interfere with IFNgamma induced expression of STAT2 and caspase-7 , and HDAC inhibitors did not preclude IFNgamma induced expression of STAT1, STAT2, and caspase-7, suggesting that HDAC inhibitors impede the expression of IFNgamma target genes whose expression depends on STAT1 but do not interfere with STAT1 independent signaling by IFNgamma "

Manually curated Databases

  • OpenBEL Selventa BEL large corpus: STAT1 (decreases, Activity)
    Evidence: inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNgamma-induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1-dependent gene activation.
  • OpenBEL Selventa BEL large corpus: STAT1 (decreases)
    Evidence: inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNgamma-induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1-dependent gene activation.
  • OpenBEL Selventa BEL large corpus: STAT1 (decreases, Activity)
    Evidence: inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNgamma-induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1-dependent gene activation.
  • OpenBEL Selventa BEL large corpus: STAT1 (decreases)
    Evidence: inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNgamma-induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1-dependent gene activation.
  • OpenBEL Selventa BEL large corpus: STAT1 (decreases, Activity)
    Evidence: inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNgamma-induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1-dependent gene activation.
  • OpenBEL Selventa BEL large corpus: STAT1 (decreases)
    Evidence: inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNgamma-induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1-dependent gene activation.
  • OpenBEL Selventa BEL large corpus: STAT1 → HDAC1 (increases, HDAC1 Activity)
    Evidence: silencing of HDAC1, HDAC2, and HDAC3 through RNA interference markedly decreased IFNgamma-driven gene activation and that overexpression of HDAC1, HDAC2, and HDAC3 enhanced STAT1-dependent transcriptional activity.
  • OpenBEL Selventa BEL large corpus: STAT1 → HDAC2 (increases, HDAC2 Activity)
    Evidence: silencing of HDAC1, HDAC2, and HDAC3 through RNA interference markedly decreased IFNgamma-driven gene activation and that overexpression of HDAC1, HDAC2, and HDAC3 enhanced STAT1-dependent transcriptional activity.
  • OpenBEL Selventa BEL large corpus: STAT1 → HDAC3 (increases, HDAC3 Activity)
    Evidence: silencing of HDAC1, HDAC2, and HDAC3 through RNA interference markedly decreased IFNgamma-driven gene activation and that overexpression of HDAC1, HDAC2, and HDAC3 enhanced STAT1-dependent transcriptional activity.