title: PASD1 promotes STAT3 activity and tumor growth by inhibiting TC45-mediated dephosphorylation of STAT3 in the nucleus.
abstract: Activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) is tightly regulated during various physiological processes, such as cell proliferation, survival, and differentiation, and aberrant STAT3 activation results in tumorigenesis. In this study, we identified the cancer/testis antigen PASD1 as a positive regulator of STAT3 activity. Overexpression of PASD1 activated STAT3 and potentiated IL-6-induced activation of STAT3, whereas knockdown of PASD1 had opposite effects. Endogenous coimmunoprecipitation experiments indicated that PASD1 interacted with STAT3 in the nucleus. Overexpression of PASD1 enhanced both basal and IL-6-induced STAT3 phosphorylation at Y705, whereas knockdown of PASD1 had opposite effects. Mechanistically, PASD1 competed with TC45, a nuclear protein tyrosine phosphatase, to associate with STAT3, thus inhibited TC45-mediated dephosphorylation of STAT3. Consistently, knockdown of PASD1 inhibited expression of many pro-oncogenic genes, leading to suppression of cell proliferation, anchorage-independent growth, cell migration, and tumor growth in nude mice. Our findings demonstrate that PASD1 serves as a critical nuclear positive regulator of STAT3-mediated gene expression and tumorigenesis.
authors.affiliation: College of Life Sciences, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan 430072, China.
authors.forename: Zhi-Sheng
authors.initials: ZS
authors.lastname: Xu
authors.affiliation: College of Life Sciences, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan 430072, China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Hebei University, Baoding 071002, China.
authors.forename: Yu-Long
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan 430072, China.
authors.forename: Tian-Tian
authors.initials: TT
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430072, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ran
authors.affiliation: College of Life Sciences, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan 430072, China.
authors.forename: Liu-Ting
authors.initials: LT
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430072, China.
authors.forename: Yan-Yi
authors.initials: YY
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan 430072, China shuh@whu.edu.cn.
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D034961:Antigens, Nuclear / Q000378:metabolism*; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D034961:Antigens, Nuclear; D015850:Interleukin-6; C515845:PASD1 protein, human; D050796:STAT3 Transcription Factor; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2
keywords: IL-6; PASD1; STAT3; signal transduction; tumorigenesis