STAT3 repressed USP7 expression is crucial for colon cancer development

Zhi, Yang; ShouJun, Huo; Shan, Yuanzhou; Liu, Haijun; Yume, Xu; Yao, Kai; Li, Xianwei; Zhang, Xueli

doi:10.1016/j.febslet.2012.06.025

Cited by 41 publications

(25 citation statements)

References 13 publications

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“…Our data are in accordance with a recent study by Yang et al (2012) that reports that, in colon tumors, IL-6 can inhibit USP7 expression in a STAT3-dependent manner. Furthermore, we show that the association of USP7 and Foxp3 is disrupted upon short-term IL-6 stimulation.…”

Section: Discussionsupporting

confidence: 94%

Stabilization of the Transcription Factor Foxp3 by the Deubiquitinase USP7 Increases Treg-Cell-Suppressive Capacity

et al. 2013

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SUMMARY Stable Foxp3 expression is required for the development of functional regulatory T (Treg) cells. Here, we demonstrate that the expression of the transcription factor Foxp3 can be regulated through the polyubiquitination of multiple lysine residues, resulting in proteasome-mediated degradation. Expression of the deubiquitinase (DUB) USP7 was found to be upregulated and active in Treg cells, being associated with Foxp3 in the nucleus. Ectopic expression of USP7 decreased Foxp3 polyubiquitination and increased Foxp3 expression. Conversely, either treatment with DUB inhibitor or USP7 knockdown decreased endogenous Foxp3 protein expression and decreased Treg-cell-mediated suppression in vitro. Furthermore, in a murine adoptive-transfer-induced colitis model, either inhibition of DUB activity or USP7 knockdown in Treg cells abrogated their ability to resolve inflammation in vivo. Our data reveal a molecular mechanism in which rapid temporal control of Foxp3 expression in Treg cells can be regulated by USP7, thereby modulating Treg cell numbers and function.

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Section: Discussionsupporting

confidence: 94%

Stabilization of the Transcription Factor Foxp3 by the Deubiquitinase USP7 Increases Treg-Cell-Suppressive Capacity

et al. 2013

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“…This transcription factor, originally identified as a DNA-binding protein, is activated by many cytokines and growth factors and represents a key component in their signaling pathway [14]. Constitutive activation of STAT3 observed in many tumors including colon cancer [15] contributes to oncogenesis by modulating the expressions of a variety of genes involved in proliferation, invasion, metastasis, and angiogenesis [16,17]. In keeping with these observations, a large body of evidence indicates that blocking STAT3 activity suppresses tumor cell growth and induces tumor cell apoptosis [18].…”

Section: Introductionmentioning

confidence: 99%

ω3-PUFAs Exert Anti-Inflammatory Activity in Visceral Adipocytes from Colorectal Cancer Patients

D’Archivio¹,

Scazzocchio²,

Giammarioli³

et al. 2013

PLoS ONE

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ObjectiveThe aim of this study was to correlate specific fatty acid profiles of visceral white adipose tissue (WAT) with inflammatory signatures potentially associated with colorectal cancer (CRC).MethodsHuman adipocytes were isolated from biopsies of visceral WAT from 24 subjects subdivided in four groups: normal-weight (BMI 22.0-24.9 Kg/m2) and over-weight/obese (BMI 26.0-40.0 Kg/m2), affected or not by CRC. To define whether obesity and/or CRC affect the inflammatory status of WAT, the activation of the pro-inflammatory STAT3 and the anti-inflammatory PPARγ transcription factors as well as the expression of adiponectin were analyzed by immunoblotting in adipocytes isolated from each group of subjects. Furthermore, to evaluate whether differences in inflammatory WAT environment correlate with specific fatty acid profiles, gas-chromatographic analysis was carried out on WAT collected from all subject categories. Finally, the effect of the ω3 docosahexaenoic acid treatment on the balance between pro- and anti-inflammatory factors in adipocytes was also evaluated.ResultsWe provide the first evidence for the existence of a pro-inflammatory environment in WAT of CRC patients, as assessed by the up-regulation of STAT3, and the concomitant decrease of PPARγ and adiponectin with respect to healthy subjects. WAT inflammatory status was independent of obesity degree but correlated with a decreased ω3-/ω6-polyunsaturated fatty acid ratio. These observations suggested that qualitative changes, other than quantitative ones, in WAT fatty acid may influence tissue dysfunctions potentially linked to inflammatory conditions. This hypothesis was further supported by the finding that adipocyte treatment with docosahexaenoic acid restored the equilibrium between STAT3 and PPARγ.ConclusionOur results suggest that adipocyte dysfunctions occur in CRC patients creating a pro-inflammatory environment that might influence cancer development. Furthermore, the protective potential of docosahexaenoic acid in re-establishing the equilibrium between pro- and anti-inflammatory factors might represent a useful tool for preventive and therapeutic strategies.

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“…For instance, mRNA and protein levels of USP7 are markedly decreased in several types of cancer [28,29]. Moreover, dys-regulation of its expression and (or) activity contributes to oncogenic transformation and is crucial for cancer development [22,29]. However, the roles of USP7 in esophagus cancer cells remain poorly understood, although we found that USP7 also positively regulated p53 abundance upon metformin treatment.…”

Section: Discussionmentioning

confidence: 90%

“…Besides, USP7 was shown to be involved in tumorigenesis [26,27]. For instance, mRNA and protein levels of USP7 are markedly decreased in several types of cancer [28,29]. Moreover, dys-regulation of its expression and (or) activity contributes to oncogenic transformation and is crucial for cancer development [22,29].…”

Section: Discussionmentioning

confidence: 99%

Metformin Inhibits Esophagus Cancer Proliferation through Upregulation of USP7

Xu¹,

Lu²

2013

Cell Physiol Biochem

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Background: Recent population studies suggest that the use of metformin is associated with reduced incidence and improved prognosis of certain cancers. Methods: In the current study, we assessed the effect of metformin on esophagus cancer cells using two cell lines (Eca-109 and TE-1 cells). Results: We found that metformin inhibited growth and decreased expression of cell-cycle regulators in these cells. Treatment with metformin was also associated with activation of AMP kinase and inhibition of mTOR/p70S6K/pS6 signaling in both cells. However, inhibition of AMPK signaling has little impact on the anti-proliferative roles of metformin. In addition, we found USP7, a positive regulator of tumor suppressor p53, as a new molecular target of metformin. Esophagus cancer cells can be protected against metformin-induced growth inhibition by small interfering RNA against USP7. Conclusion: These results provide evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent population studies and justify further work to explore potential roles for it in esophagus cancer prevention and treatment.

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STAT3 repressed USP7 expression is crucial for colon cancer development

Cited by 41 publications

References 13 publications

Stabilization of the Transcription Factor Foxp3 by the Deubiquitinase USP7 Increases Treg-Cell-Suppressive Capacity

Stabilization of the Transcription Factor Foxp3 by the Deubiquitinase USP7 Increases Treg-Cell-Suppressive Capacity

ω3-PUFAs Exert Anti-Inflammatory Activity in Visceral Adipocytes from Colorectal Cancer Patients

Metformin Inhibits Esophagus Cancer Proliferation through Upregulation of USP7

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