STAT3 signaling drives EZH2 transcriptional activation and mediates poor prognosis in gastric cancer

Abstract

BackgroundSTAT3 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).MethodsSTAT3, 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.ResultsHyper-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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0561-z) contains supplementary material, which is available to authorized users.

STAT3 activates MSK1-mediated histone H3 phosphorylation to promote NFAT signaling in gastric carcinogenesis

“…With interaction, histone-modifying enzymes also modify STAT3, including acetylation and methylation changes, which has important consequences for target gene transcription 42 . Interestingly, it was recently reported that STAT3 can directly regulate the transcription of some crucial epigenetic enzymes (DNMT1, EZH2, JMJD3), adding another functional level of STAT3 as an important regulator of global epigenetic modifications and chromatin accessibilities [21][22][23] . In the present study, we uncovered a novel interplay between STAT3 and the chromatin-associated kinase MSK1 in gastric carcinogenesis: STAT3 drives MSK1 transcriptional activation and affects numerous gene alterations through histone H3 phosphorylation; MSK1 modulates the activation of STAT3 by phosphorylating its Ser727 residue, thus forming a positive feedback mechanism between these two molecules.…”

“…By regulating the expression of numerous oncogenic genes, STAT3 promotes the development of different types of cancer. Through epigenetic mechanisms, activated STAT3 has been reported to modulate the expression of DNA methyltransferases and histone methylases or demethylases in hematological malignancies and solid tumors [21][22][23] . A regulatory complex was also identified between STAT3 and those chromatin-associated enzymes in epigenetic silencing or activation of vital tumorpromoting genes [24][25][26][27] .…”

The regulatory proteins DSCR6 and Ezh2 oppositely regulate Stat3 transcriptional activity in mesoderm patterning during Xenopus development

“…Thus, it is clear that DSCR6 and Ezh2 exerts opposite activities to post-translationally regulate Stat3 function in DV patterning. However, Stat3 signaling was also able to drive Ezh2 transcriptional activation in gastric cancer (35). To see if this occurs during early development, we overexpressed Stat3C in ectoderm explants and analyzed the expression of Ezh2 and Dscr6 at early gastrula stage by RT-PCR.…”

EZH2 promotes invasion and tumour glycolysis by regulating STAT3 and FoxO1 signalling in human OSCC cells

“…The enhancer of zeste homolog 2 (EZH2), known as a member of the polycomb group (PcG) proteins, is a histone methyltransferase closely correlated with tumour aggressiveness in a variety of human malignancies, including oral, nasopharyngeal, gastric, hepatocellular, colon, renal, prostate and lung cancers. [14][15][16][17][18][19][20][21] In a study of head and neck squamous cell carcinoma, EZH2 was associated with tumour aggressiveness via regulating EMT, and EZH2 silencing increased E-cadherin while decreasing N-cadherin and vimentin. 22 Another study of laryngeal squamous cell carcinoma revealed that EZH2 could promote invasion and metastasis via EMT through catalysing trimethylation of lysine 27 in histone 3 (H3K27me3) and consequently inducing transcriptional repression of E-cadherin.…”

“…The enhancer of zeste homolog 2 (EZH2), known as a member of the polycomb group (PcG) proteins, is a histone methyltransferase closely correlated with tumour aggressiveness in a variety of human malignancies, including oral, nasopharyngeal, gastric, hepatocellular, colon, renal, prostate and lung cancers . In a study of head and neck squamous cell carcinoma, EZH2 was associated with tumour aggressiveness via regulating EMT, and EZH2 silencing increased E‐cadherin while decreasing N‐cadherin and vimentin .…”