title: STAT3 signaling drives EZH2 transcriptional activation and mediates poor prognosis in gastric cancer.
abstract: STAT3 signaling plays the pivotal role in tumorigenesis through EZH2 epigenetic modification, which enhanced STAT3 activity by increased tyrosine phosphorylation of STAT3. Here, another possible feedback mechanism and clinical significance of EZH2 and STAT3 were investigated in gastric cancer (GC).
  
  
  
  STAT3, p-STAT3 (Tyr 705) and EZH2 expression were examined in 63 GC specimens with matched normal tissues by IHC staining. EZH2 and STAT3 were also identified in five GC cell lines using RT-PCR and western blot analyses. p-STAT3 protein was detected by western blotting. In order to investigate whether EZH2 expression was directly regulated by STAT3, EZH2 expression was further detected using siRNA for STAT3 or IL-6 stimulation, with dual luciferase reporter analyses, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. The clinical significance of STAT3, p-STAT3 and EZH2 expression was evaluated by multi-factor COX regression and Kaplan-Meier analyses.
  
  
  
  Hyper-activation of STAT3, p-STAT3 and EZH2 expression were observed in GC cells and tissues. STAT3 signaling was correlated with EZH2 expression in GC (R = 0.373, P = 0.003), which was consistent with our data showing that STAT3 as the transcriptional factor enhanced EZH2 transcriptional activity by binding the relative promoter region (-214 ~ -206). STAT3 was an independent signature for poor survival (P = 0.002). Patients with STAT3+/EZH2+or p-STAT3+/EZH2+had a worse outcome than others (P < 0.001); Besides, high levels of STAT3 and EZH2 was associated with advanced TNM staging (P = 0.017). Moreover, treatment with a combination of siSTAT3 and EZH2-specific inhibitor, 3-deazaneplanocin A (DZNEP), increased the apoptotic ratio of cells. It is benefit for targeting STAT3-EZH2 interplay in GC treatment.
  
  
  
  Our results indicate that STAT3 status mediated EZH2 upregulation, associated with advanced TNM stage and poor prognosis, suggesting that combination with knockdown of STAT3 and EZH2 inhibitor might be a novel therapy in GC treatment. Collectively, STAT3, p-STAT3 and EZH2 expression were provided for the precision medicine in GC patients.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute , 52 Fucheng Road, Haidian District, Beijing, 100142, China.
authors.forename: Yuan-Ming
authors.initials: YM
authors.lastname: Pan
authors.affiliation: Department of Gastroenterology Surgery, Surgical Oncology Laboratory, People's Hospital, Peking University, Beijing, 100044, China.|Department of Cardiology, Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
authors.forename: Cheng-Gang
authors.initials: CG
authors.lastname: Wang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute , 52 Fucheng Road, Haidian District, Beijing, 100142, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute , 52 Fucheng Road, Haidian District, Beijing, 100142, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xing
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute , 52 Fucheng Road, Haidian District, Beijing, 100142, China.
authors.forename: Jian-Tao
authors.initials: JT
authors.lastname: Cui
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute , 52 Fucheng Road, Haidian District, Beijing, 100142, China.
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Li
authors.affiliation: Department of Oncology/Institute for Cancer Research, Baotou Central Hospital, Inner Mongolia, 014040, China.
authors.forename: De-Dong
authors.initials: DD
authors.lastname: Yu
authors.affiliation: Department of Oncology/Institute for Cancer Research, Baotou Central Hospital, Inner Mongolia, 014040, China.
authors.forename: Shu-Bin
authors.initials: SB
authors.lastname: Wang
authors.affiliation: Department of Oncology/Institute for Cancer Research, Baotou Central Hospital, Inner Mongolia, 014040, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Gastroenterology Surgery, Surgical Oncology Laboratory, People's Hospital, Peking University, Beijing, 100044, China.
authors.forename: Ying-Jiang
authors.initials: YJ
authors.lastname: Ye
authors.affiliation: Department of Oncology/Institute for Cancer Research, Baotou Central Hospital, Inner Mongolia, 014040, China. yunwu_baotou@sina.com.|Department of Oncology/Institute for Cancer Research, Baotou Central Hospital, Baotou, 014040, People's Republic of China. yunwu_baotou@sina.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology Surgery, Surgical Oncology Laboratory, People's Hospital, Peking University, Beijing, 100044, China. shanwang11@gmail.com.|Department of Gastroenterological Surgery, Surgical Oncology Laboratory, People's Hospital, Beijing University, No. 11, South Xizhimen Street, Beijing, 100044, People's Republic of China. shanwang11@gmail.com.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute , 52 Fucheng Road, Haidian District, Beijing, 100142, China. youyonglu@hsc.pku.edu.cn.
authors.forename: You-Yong
authors.initials: YY
authors.lastname: Lu
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D016019:Survival Analysis; D015533:Transcriptional Activation
chemical_list: D050796:STAT3 Transcription Factor; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: 3-deazaneplanocin A; EZH2; Gastric cancer; Prognosis; STAT3; p-STAT3