STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor

Wang, Yuxin; Boxel-Dezaire, Anette H.H. van; Cheon, HyeonJoo; Yang, Jinbo; Stark, George R.

doi:10.1073/pnas.1315862110

Cited by 251 publications

(238 citation statements)

References 37 publications

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“…The biphasic pattern of Y705 phosphorylation of STAT3 in Fig. 4C is in accord with our previous observations (17). The IL-6-induced expression of three genes whose expression is inhibited by the K49R mutation, SERPINA1, SOCS3, and GADD45G, also was inhibited when EZH2 was knocked down (compare Fig.…”

Section: Stat3supporting

confidence: 91%

STAT3-driven transcription depends upon the dimethylation of K49 by EZH2

Dasgupta¹,

Dermawan²,

Willard

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

108

114

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Several transcription factors, including p53, NF-κB, and STAT3, are modified by the same enzymes that also modify histones, with important functional consequences. We have identified a previously unrecognized dimethylation of K49 of STAT3 that is crucial for the expression of many IL-6-dependent genes, catalyzed by the histone-modifying enzyme enhancer of zeste homolog 2 (EZH2). Loss of EZH2 is protumorigenic in leukemias, but its overexpression is protumorigenic in solid cancers. Connecting EZH2 to a functionally important methylation of STAT3, which is constitutively activated in many tumors, may help reveal the basis of the opposing roles of EZH2 in liquid and solid tumors and also may identify novel therapeutic opportunities.posttranslational modification | histone methyltransferase | gene expression S TAT3 is activated in 70% of all solid and hematological tumors (1, 2), where it stimulates proliferation, survival, angiogenesis, invasion, and tumor-promoting inflammation. Recently, STAT3 also was found to have an important role in maintaining cancer stem cells, both in vitro and in mouse tumor models, indicating that it is integrally involved in tumor initiation, progression, and maintenance (3). IL-6-induced constitutive activation of STAT3 was observed in neoplastic gastric tissue and is positively correlated with tumor progression (4), and the expression of tyrosine-phosphorylated STAT3 is associated with poor prognosis in colorectal cancer, independent of the mutation status of MSI, CIMP, BRAF, or KRAS (5). The STAT3 gene is rarely mutated in cancer but rather is activated by members of the IL-6 family of cytokines, receptor tyrosine kinases, mutated JAKs, or oncogenic cellular tyrosine kinases, such as SRC (6). Because STAT3 is constitutively activated during disease progression and metastasis, it is a promising therapeutic target. Even though transcription factors are difficult drug targets, accumulating evidence for the crucial roles of posttranslational modifications of transcription factors in mediating target gene expression provides an opportunity to develop drugs against the modifying enzymes rather than against the transcription factors themselves.STAT3 is activated primarily by phosphorylation of Y705 (7) and secondarily by phosphorylation of S727 (8). The acetylation of STAT3 at K685 (9, 10) has been shown recently to have little or no effect on IL-6-dependent gene expression (11). Ray et al. (12) reported that IL-6-induced gene expression requires p300-mediated acetylation of K49 and K87 and that monoubiquitination at K97 is a key mediator of BRD4-dependent gene expression (13). Like NF-κB and p53, STAT3 is reversibly methylated on lysine residues by histone-modifying enzymes, with important functional consequences (14). Furthermore, STAT3 is known to be di-or trimethylated on K140 or K180 by the histone methyltransferase SET9 (SET domain containing lysine methyltransferase 9) or EZH2 (enhancer of zeste homolog 2), respectively (15, 16). Here we show that IL-6-dependent, previously unident...

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Section: Stat3supporting

confidence: 91%

STAT3-driven transcription depends upon the dimethylation of K49 by EZH2

Dasgupta¹,

Dermawan²,

Willard

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

108

114

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“…These two proteins can also affect signaling pathways indirectly through regulation of downstream cytokines. IL-6 and TNF-α play particularly important roles, because they can form feedback loops with STAT3 and NF-κB, respectively (29,30). We found that IL-6 treatment not only increased the phosphorylation of STAT3 but also increased the expression of SMYD2 ( Figure 6E), and that treatment with TNF-α also increased the phosphorylation of p65 and the expression of SMYD2 ( Figure 6F).…”

Section: Silencing Smyd2 Decreased Phosphorylation and Activation Of mentioning

confidence: 76%

Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease

Li¹,

Fan²,

Zhou³

et al. 2017

Journal of Clinical Investigation

119

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Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in PKD1 and PKD2 genes. Recent work suggests that epigenetic modulation of gene expression and protein function may play a role in ADPKD pathogenesis. In this study, we identified SMYD2, a SET and MYND domain protein with lysine methyltransferase activity, as a regulator of renal cyst growth. SMYD2 was upregulated in renal epithelial cells and tissues from Pkd1-knockout mice as well as in ADPKD patients. SMYD2 deficiency delayed renal cyst growth in postnatal kidneys from Pkd1 mutant mice. Pkd1 and Smyd2 doubleknockout mice lived longer than Pkd1-knockout mice. Targeting SMYD2 with its specific inhibitor, AZ505, delayed cyst growth in both early-and later-stage Pkd1 conditional knockout mouse models. SMYD2 carried out its function via methylation and activation of STAT3 and the p65 subunit of NF-κB, leading to increased cystic renal epithelial cell proliferation and survival. We further identified two positive feedback loops that integrate epigenetic regulation and renal inflammation in cyst development: SMYD2/IL-6/STAT3/SMYD2 and SMYD2/TNF-α/NF-κB/SMYD2. These pathways provide mechanisms by which SMYD2 might be induced by cyst fluid IL-6 and TNF-α in ADPKD kidneys. The SMYD2 transcriptional target gene Ptpn13 also linked SMYD2 to other PKD-associated signaling pathways, including ERK, mTOR, and Akt signaling, via PTPN13-mediated phosphorylation.

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“…In contrast, the activation of STAT1 by IFNγ stimulation resulted in potentiation of miR‐7 transcriptional activity; here, we suggest that this was through ISRE, ISGF3G, and upstream STAT1 binding sites. Levels of STAT3 bound to the miR‐7 promoter probe, observed in E2‐treated young fibroblasts, may be causative of increased EGFR expression and activity, as recent research has identified an increase in STAT3 signaling in the presence of EGFR/IL6R association and co‐activation (Wang et al ., 2013). STAT1 forms complexes with STAT2 and IRF9 to activate ISGF3G/ISRE (Darnell et al ., 1994); however, STAT3 suppressed STAT1‐dependent gene activation and inhibited STAT1 heterodimer formation (Ho & Ivashkiv, 2006).…”

Section: Discussionmentioning

confidence: 99%

17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation

et al. 2016

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SummaryAge‐related defects in fibroblast differentiation and functionality were previously shown to be associated with impaired hyaluronan (HA) synthase 2 (HAS2) and epidermal growth factor receptor (EGFR) function, as a result of upregulated microRNA‐7 (miR‐7) expression. In aging fibroblasts, inhibiting miR‐7 prevented the dysregulation of the HA‐mediated CD44/EGFR signaling pathway. Here, we investigated transcriptional upregulation of miR‐7 and implicated the age‐associated over‐activation of JAK/STAT1 as a primary candidate. STAT1 binding sites were identified on the putative miR‐7 promoter and stimulation of fibroblasts with the inflammatory cytokine, interferon‐γ (IFN‐γ), significantly increased miR‐7 transcriptional activity and resulted in upregulated miR‐7 and loss of EGFR. Additionally, we demonstrated a role for the anti‐inflammatory steroid, 17β‐estradiol (E2), in the attenuation of miR‐7 expression. E2 stimulation promoted estrogen receptor (ER) interactions with the miR‐7 putative promoter and suppressed miR‐7 expression. E2 also attenuated STAT1 expression and activity. Furthermore, treatments with E2 restored fibroblast functionality, including proliferation, migration and differentiation, key events in effective wound healing. In light of our findings, we propose that the regulation of miR‐7 by pro‐ and anti‐inflammatory mediators plays a wider role than previously thought. The modulation of fibroblast functions and ultimately wound healing by miR‐7 activators or inhibitors could provide realistic targets for the restoration of chronic wound healing capabilities in the elderly.

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STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor

Cited by 251 publications

References 37 publications

STAT3-driven transcription depends upon the dimethylation of K49 by EZH2

STAT3-driven transcription depends upon the dimethylation of K49 by EZH2

Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease

17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation

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