title: Phosphorylated STAT3 physically interacts with NPM and transcriptionally enhances its expression in cancer.
abstract: The signal transducer and activator of transcription 3 (STAT3) can be activated by the tyrosine kinase domain of the chimeric protein nucleophosmin/anaplastic lymphoma kinase (NPM/ALK), and has a pivotal role in mediating NPM/ALK-related malignant cell transformation. Although the role of STAT3 and wild-type NPM in oncogenesis has been extensively investigated, the relationship between both molecules in cancer remains poorly understood. In the present study, we first demonstrate that STAT3 phosphorylation at tyrosine 705 is accompanied by a concomitant increase in the expression level of NPM. Nuclear co-translocation of phosphorylated STAT3 with NPM can be triggered by interferon-alpha (IFN-α) stimulation of Jurkat cells and phosphorylated STAT3 co-localizes with NPM in cancer cells showing constitutive STAT3 activation. We further demonstrate that STAT3 phosphorylation can transcriptionally mediate NPM upregulation in IFN-α-stimulated Jurkat cells and is responsible for maintaining its expression in cancer cells showing constitutive STAT3 activation. Inhibition of STAT3 phosphorylation or knockdown of NPM expression abrogates their simultaneous transnuclear movements. Finally, we found evidence for a physical interaction between NPM and STAT3 in conditions of STAT3 activation. In conclusion, NPM is a downstream effector of the STAT3 signaling, and can facilitate the nuclear entry of phosphorylated STAT3. These observations might open novel opportunities for targeting the STAT3 pathway in cancer.
authors.affiliation: 1] Laboratory of Medical and Molecular Oncology (LMMO), Department of Medical Oncology, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium [2] Department of General Surgery, The first People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai, China [3] Department of Medical Oncology, Oncologisch Centrum of the Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Z
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: J L
authors.initials: JL
authors.lastname: Aerts
authors.affiliation: 1] Department of Medical Oncology, Oncologisch Centrum of the Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium [2] Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: J J
authors.initials: JJ
authors.lastname: Pen
authors.affiliation: Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Heirman
authors.affiliation: Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Breckpot
authors.affiliation: 1] Laboratory of Medical and Molecular Oncology (LMMO), Department of Medical Oncology, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium [2] Department of Medical Oncology, Oncologisch Centrum of the Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: De Grève
mesh_terms: D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D009369:Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D000090243:Nucleophosmin; D010766:Phosphorylation; D021381:Protein Transport; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D016898:Interferon-alpha; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000090243:Nucleophosmin