De-SUMOylation of FOXC2 by SENP3 promotes the epithelial-mesenchymal transition in gastric cancer cells

Ren, Yan; Liu, Ke Jia; Wang, Ming; Yu, You; Yang, Kai; Chen, Qin; Yu, Bin; Wang, Wei; Li, Qi Wei; Wang, Jian; Hou, Zhao Yuan; Fang, Jing; Yeh, Edward T.H.; Yang, Jie; Yi, Jing

doi:10.18632/oncotarget.2197

Cited by 53 publications

(49 citation statements)

References 43 publications

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“…prostate Overexpression of SENP1 [131,132] Overexpression of SENP3 [101] colon Overexpression of SENP1 [133] Overexpression of SENP3 [134] liver Downregulation of SENP2 [135] Overexpression of SENP6 [136] bladder Downregulation of SENP2 [137] gastric Overexpression of SENP3 [138] Trends Biochem Sci. Author manuscript; available in PMC 2016 June 01.…”

Section: Figure 2 Sumoylation Of Important Cell Cycle Regulatorsmentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

246

211

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SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. KeywordsSUMO; mitosis; SUMOylation; cancer; cell cycle SUMO: a ubiquitin-like modifier that regulates nuclear processesThe complexity of eukaryotic proteomes is widely expanded by protein processing and a vast array of posttranslational modifications. The quick and reversible attachment of small modifiers is essential for all cellular processes and ensures dynamic and rapid responses to extracellular and intracellular stimuli. Apart from chemical modifications such as phosphorylation [1], glycosylation [2] and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the activity, localization, half-life or interactome of the target protein. Since the initial discovery of ubiquitin, the founding member of these small protein posttranslational modifications in 1975 [4], a large family of structurally related ubiquitin-like modifiers has been uncovered including SUMO, Nedd8, ISG15, FAT10, FUB1, UFM1, URM1, Atg12 and Atg8 [5][6][7][8]. The attachment of these small ubiquitin-like modifiers is catalysed by an enzymatic cascade consisting of an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), and can be reversed by specific and cell cycle control. It is therefore not surprising that SUMO signal transduction has been implicated in the development of several different cancer types, which could potentially be exploited in anti-cancer therapies. In this review we will focus on the role of SUMO in cell cycle regulation, specifically highlighting its physiological relevance and its deregulation in cancer. Recent progress includes the identification of many novel SUMO substrates with important roles in cell cycle progression using proteomic approaches, and the demonstration that different mouse cancer models are dependent on a functioning SUMOylation system. Switching of SUMOylation in these cancer models caused a proliferation block of the cancer cells, showing that SUMO conjugating enzymes are potential drug targets. Europe PMC Funders Group Twenty years of SUMO research in cell cycle controlSUMO was linked to cell cycle progression even before the identification of the small protein modifier itself. Twenty years ago, the yeast SUMO conjugating enzyme Ubc9 was first proposed to be a ubiquitin conjugating enzyme. Ubc9 was s...

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Section: Figure 2 Sumoylation Of Important Cell Cycle Regulatorsmentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

246

211

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“…7,8 In gastric cancer cells, SENP3, which is a redox-sensitive molecule mediating the epithelial-mesenchymal transition (EMT), promotes the EMT by De-SUMOylation of Forkhead Box C2 (FOXC2). 9 It is reported that SENP3 is elevated in ovarian cancer than normal tissues, as well as prostate, lung, rectal, and colon carcinomas. 5 Another study shows that a single-nucleotide polymorphism (SNP) of SENP3 rs6608 may perform as predictors of risk of EOC and invasiveness.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of SENP3/SMT3IP1 promotes epithelial ovarian cancer progression and forecasts poor prognosis

Cheng

Jin

et al. 2017

Tumour Biol.

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As a crucial member of the small ubiquitin-like modifier system, SUMO-specific protease 3, was identified to be essential for cell proliferation and ribosomal RNA processing. Recent studies showed that SUMO-specific protease 3 was elevated in ovarian cancer compared to normal tissue samples. However, the connection between SUMO-specific protease 3-specific expression and clinicopathological parameters of epithelial ovarian cancer, as well as the physiologically potential role of SUMO-specific protease 3 in epithelial ovarian cancer remained unclear. In this study, an analysis of 124 paraffin-embedded slices by immunohistochemistry indicated that SUMO-specific protease 3 expression was positively correlated with the International Federation of Gynecology and Obstetrics stages (p = 0.025), tumor grade (p = 0.004), and lymph node metastasis (p = 0.001) and was also a critical prognostic factor for the overall survival of epithelial ovarian cancer patients, as revealed by Kaplan-Meier curve analysis. Knockdown of SUMO-specific protease 3 weakened the proliferation, migration, and invasion capability of ovarian cancer cells, down-regulated the expression of Proliferating Cell Nuclear Antigen, Forkhead Box C2, and N-cadherin, and resulted in upregulation of p21 and E-cadherin. Consistent with our results, SUMO-specific protease 3 had been verified to promote cell proliferation, metastasis, and tumorigenesis in multiple malignant cancers, which was a redox-sensitive molecule mediating the epithelial-mesenchymal transition. Collectively, our findings for the first time specifically supported that SUMO-specific protease 3 might play an important role in the regulation of epithelial ovarian cancer progression and could serve as a potential biomarker for prognosis as well as provide a promising therapeutic target against epithelial ovarian cancer.

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“…47, 48 Increased SENP3 regulates the functions of its substrates in cancer cells through the removal of SUMO2/3 modification, leading to enhanced cell proliferation, tumorigenesis, angiogenesis and epithelial–mesenchymal transition. 47, 48, 49, 50 Many SENP3 substrates are transcription factors or co-factors. 47, 50 Our preliminary data have implicated a potential interaction between SENP3 and STAT3.…”

Section: Introductionmentioning

confidence: 99%

SUMOylation and SENP3 regulate STAT3 activation in head and neck cancer

Zhou

Wang

et al. 2016

Oncogene

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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.

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De-SUMOylation of FOXC2 by SENP3 promotes the epithelial-mesenchymal transition in gastric cancer cells

Cited by 53 publications

References 43 publications

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Upregulation of SENP3/SMT3IP1 promotes epithelial ovarian cancer progression and forecasts poor prognosis

SUMOylation and SENP3 regulate STAT3 activation in head and neck cancer

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