title: N-terminal truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in prostate cancer cells.
abstract: Transcription factor Stat5a/b is critical for prostate cancer cell survival and for prostate xenograft tumor growth. In addition, the Stat5a/b signaling pathway may contribute to progression of organ-confined prostate cancer to castration-resistant and/or metastatic disease. Expression of nuclear Stat5a/b is clustered to high grade human prostate cancers, and nuclear Stat5a/b in primary prostate cancer predicts early disease recurrence after initial treatment. Here, we show by Western blotting and electromobility shift assay that Stat5a/b protein in human prostate cancer is N-terminally truncated. This short form of Stat5a/b is generated post-translationally in vivo in prostate cancer cells and is the predominant form of Stat5a/b that binds to DNA. We further demonstrate by mutagenesis and co-immunoprecipitations that the N-domain of Stat5a/b is required for binding to PIAS3, and that PIAS3 inhibits transcriptional activity of Stat5a/b in breast cancer cells but not in prostate cancer cells. Thus, the proteolytic cleavage of the N-terminus of Stat5a/b may be a mechanism by which Stat5 evades the transcriptional repression by PIAS3 in prostate cancer cells, and results in increased Stat5-driven gene expression and prostate cancer progression.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Ayush
authors.initials: A
authors.lastname: Dagvadorj
authors.forename: Shyh-Han
authors.initials: SH
authors.lastname: Tan
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liao
authors.forename: Jianwu
authors.initials: J
authors.lastname: Xie
authors.forename: Martti
authors.initials: M
authors.lastname: Nurmi
authors.forename: Kalle
authors.initials: K
authors.lastname: Alanen
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.forename: Tuomas
authors.initials: T
authors.lastname: Mirtti
authors.forename: Marja T
authors.initials: MT
authors.lastname: Nevalainen
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D025521:Tumor Suppressor Proteins