title: SUMOylation and SENP3 regulate STAT3 activation in head and neck cancer.
abstract: Hyperphosphorylation of signal transducer and activator of transcription 3 (STAT3) has been found in various types of human cancers, including head and neck cancer (HNC). Although smoking is critical in the development and progression of HNC, how tobacco components activate STAT3 is unclear. We demonstrated that exposure of HNC cell lines to a tobacco extract induced a rapid Y705 phosphorylation of STAT3 and a rapid increase in the SUMO protease SENP3 that depended on a simultaneous increase in reactive oxygen species. We identified that SUMOylation at the lysine 451 site facilitated STAT3 binding to the phosphatase TC45 through an SUMO-interacting motif of TC45. SENP3 could thus enhance STAT3 phosphorylation by de-conjugating the SUMO2/3 modification of STAT3. Knocking-down of SENP3 greatly impaired basal and induced STAT3 phosphorylation by tobacco extract or interleukin 6. A correlation between SENP3 protein levels and STAT3 Y705 phosphorylation levels in human laryngeal carcinoma specimens was found, which was more significant in the specimens derived from the smoker patients and with poor clinicopathological parameters. Our data identified SUMOylation as a previously undescribed post-translational modification of STAT3 and SENP3 as a critical positive modulator of tobacco- or cytokine-induced STAT3 activation. These findings provide novel insights into the hyperphosphorylation of STAT3 in development of HNC.
authors.affiliation: Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Department of Otolaryngology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Y E
authors.initials: YE
authors.lastname: Chin
authors.affiliation: Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: E T H
authors.initials: ET
authors.lastname: Yeh
authors.affiliation: Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Yi
mesh_terms: D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007822:Laryngeal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D009367:Neoplasm Staging; D009602:Nitrosamines / Q000494:pharmacology; D010766:Phosphorylation; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D058207:Sumoylation; D014158:Transcription, Genetic; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D009602:Nitrosamines; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C117909:SUMO2 protein, human; C492189:SUMO3 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014452:Ubiquitins; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D003546:Cysteine Endopeptidases; C499718:SENP3 protein, human