Requirement of histone deacetylase activity for signaling by STAT1.
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.
Klampfer
Lidija
L
Albert Einstein Cancer Center, Montefiore Medical Center, Department of Oncology, Bronx, New York 10467, USA. lklampf@aecom.yu.edu
Huang
Jie
J
Swaby
Laurie-Anne
LA
Augenlicht
Leonard
L
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis; D015153:Blotting, Western; D002087:Butyrates / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D017930:Genes, Reporter; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry; D000077337:Vorinostat; D051020:bcl-X Protein; D000099186:Histone Deacetylase 3
D002087:Butyrates; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D007371:Interferon-gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D012694:Serine; D015534:Trans-Activators; D014443:Tyrosine; D000077337:Vorinostat; D051020:bcl-X Protein; D000099186:Histone Deacetylase 3; C494811:BCL2L1 protein, human; C494079:STAT1 protein, human; C012589:trichostatin A; C110550:HDAC1 protein, human