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.
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Acknowledgements
We gratefully acknowledge technical and administrative assistance from Dr Erik Teugels, Dr Zhihai Peng, Eddy Himpe, Bill Roskams, Geert Stangé, Petra Roman, Elsy Vaeremans, Cleo Goyvaerts. We sincerely thank Dr Jacqueline Bromberg, Dr Dorothee Herlyn, Dr Pravin Sehgal, Dr Qishen Pang for their provision of shSTAT3, shNPM, GFP-STAT3 Y705A, and NPM promoter vectors. We also express our gratitude to Dr Georges De Bruyne and Dr Peter de Witte for providing MDA-MB-231, MDA-MB-435 and MDA-MB-468 cell lines. This work was supported by the Stichting Tegen Kanker Belgium, FWO-Vlaanderen (FWOAL335, FWOAL455 and FWOWO35) and the VUB (OZR1144). ZR is a Ph. D student supported by Chinese Scholarship Council (CSC)-VUB joint scholarship. JLA and KB are postdoctoral fellows of the Foundation of Scientific Research Flanders (FWO-V).
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Ren, Z., Aerts, J., Pen, J. et al. Phosphorylated STAT3 physically interacts with NPM and transcriptionally enhances its expression in cancer. Oncogene 34, 1650–1657 (2015). https://doi.org/10.1038/onc.2014.109
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DOI: https://doi.org/10.1038/onc.2014.109
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