HDAC3 influences phosphorylation of STAT3 at serine 727 by interacting with PP2A.
Signal transducer and activator of transcription 3 (STAT3), which mediates biological actions in many physiological processes, is activated by cytokines and growth factors, and has been reported to be involved in the pathogenesis of various human diseases. Here, we show that treatment of HeLa cells with a histone deacetylase (HDAC) inhibitor, trichostatin A, or small-interfering RNA (siRNA)-mediated repression of HDAC3, enhances phosphorylation of STAT3 at Ser727. Furthermore, dephosphorylation of STAT3 at Ser727 by protein phosphatase 2A (PP2A) was restored by treatment of cells with HDAC3 siRNA. We further found that formation of a complex between STAT3 and PP2A was enhanced in the presence of HDAC3. Importantly, small-interfering RNA-mediated repression of both HDAC3 and PP2A effectively enhanced leukemia inhibitory factor (LIF)-induced STAT3 activation. These results indicate that HDAC3 may act as a scaffold protein for PP2A to regulate the LIF/STAT3-mediated signaling pathway.
Togi
Sumihito
S
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku Kita 12 Nishi 6, Sapporo 060-0812, Japan.
Kamitani
Shinya
S
Kawakami
Shiho
S
Ikeda
Osamu
O
Muromoto
Ryuta
R
Nanbo
Asuka
A
Matsuda
Tadashi
T
D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D000099186:Histone Deacetylase 3
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D008156:Luciferases; D054648:Protein Phosphatase 2; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D012694:Serine; D000099186:Histone Deacetylase 3; C012589:trichostatin A