The ubiquitination ligase SMURF2 reduces aerobic glycolysis and colorectal cancer cell proliferation by promoting ChREBP ubiquitination and degradation

Li, Yakui; Yang, Dianqiang; Tian, Na; Zhang, Ping; Zhu, Yemin; Meng, Jian; Feng, Ming; Lu, Ying; Liu, Qi; Tong, Lingfeng; Hu, Lei; Zhang, Lukuan; Yang, James Y.; Wu, Lifang; Tong, Xuemei

doi:10.1074/jbc.ra119.007508

Cited by 29 publications

(26 citation statements)

References 37 publications

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“…Smurf2 overexpression plays key roles in several physiological and pathological processes, 17‐21,53 but the mechanisms that control Smurf2 expression have not been clearly elucidated. MicroRNA‐322 and microRNA‐503 were identified as novel factors that regulate Smurf2 expression at the translational level 54 .…”

Section: Discussionmentioning

confidence: 99%

“…SMAD‐specific E3 ubiquitin protein ligase 2 (Smurf2) is a novel E3 ubiquitin enzyme that was initially identified as a negative regulator of the bone morphogenetic protein and transforming growth factor beta signaling pathways 17 . Overexpression of Smurf2, which promotes metastasis by enhancing PI3K/AKT‐dependent cell proliferation and invasion, has been observed in various cancers, 18,19 whereas another series of studies showed that inactivation of Smurf2 might trigger the mesenchymal‐to‐epithelial transition (MET) and indicated that Smurf2 functions as a potent antitumor factor that prevents carcinogenesis in both mouse models and human cells 20,21 . These studies have described the importance and variability of Smurf2 in cell physiology and disease, but the question of whether Smurf2 participates in angiogenesis remains largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

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SMAD-specific E3 ubiquitin ligase 2 promotes angiogenesis by facilitating PTX3 degradation in MSCs from patients with ankylosing spondylitis

Wen

Cai

et al. 2021

Stem Cells

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Dysregulated angiogenesis of mesenchymal stem cells (MSCs) is closely related to inflammation and disrupted bone metabolism in patients with various autoimmune diseases. However, the role of MSCs in the development of abnormal angiogenesis in patients with ankylosing spondylitis (AS) remains unclear. In this study, we cultured human umbilical vein endothelial cells (HUVECs) with bone marrow-derived MSCs from patients with AS (ASMSCs) or healthy donors (HDMSCs) in vitro. Then, the cocultured HUVECs were assayed using a cell counting kit-8 (CCK-8) to evaluate the cell proliferation. A wound healing assay was performed to investigate cell migration, and a tube formation assay was conducted to determine the angiogenesis efficiency. ASMSCs exhibited increased angiogenesis, and increased expression of SMAD-specific E3 ubiquitin ligase 2 (Smurf2) in MSCs was the main cause of abnormal angiogenesis in patients with AS. Downregulation of Smurf2 in ASMSCs blocked angiogenesis, whereas overexpression of Smurf2 in HDMSCs promoted angiogenesis. The pro-angiogenic effect of Smurf2 was confirmed by the results of a Matrigel plug assay in vivo. By functioning as an E3 ubiquitin ligase in MSCs, Smurf2 regulated the levels of pentraxin 3 (PTX3), which has been shown to suppress angiogenesis through the PTX3-fibroblast growth factor 2 pathway. Moreover, Smurf2 transcription was regulated by activating transcription factor 4-induced endoplasmic reticulum stress. In conclusion, these results identify novel roles of Smurf2 in negatively regulating PTX3 stability and promoting angiogenesis in ASMSCs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SMAD-specific E3 ubiquitin ligase 2 promotes angiogenesis by facilitating PTX3 degradation in MSCs from patients with ankylosing spondylitis

Wen

Cai

et al. 2021

Stem Cells

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“…Smurf2 is a member of the homologous to E6-AP carboxyl terminus family of E3 ubiquitin ligases that is important for the ubiquitination of several substrates, including SMAD2, SMAD7 and YY1 31 . Recent studies reported that Smurf2 was responsible for the ubiquitination of FUBP1, while low expression of Smurf2 was signi cantly associated with impaired overall survival of CRC patients 32,33 . Our data showed that the expression of FUBP1 was negatively related to Smurf2 in KRAS wild-type patients.…”

Section: Discussionmentioning

confidence: 99%

FUBP1 Promotes Colorectal Cancer Stemness and Metastasis via DVL1-Mediated Activation of Wnt/β-Catenin Signaling

Yin

Gao²,

Xie³

et al. 2021

Preprint

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Background: Most colorectal cancer (CRC) patients die from distant metastasis. Approximately 50% of CRC patients develop liver metastases, while 10% to 30% of patients appear pulmonary metastases. The occurrence of metastasis is considered to be almost exclusively driven by cancer stem cells (CSCs) formation. However, the key molecules that confer the stem-transformation of CRC and subsequent metastasis remain unclear.Methods: FUBP1 was screened in CRC CSCs by mass spectrometry and was examined by immunohistochemistry in a cohort of CRC tissues. The stemness induction and mechanism of FUBP1 were elucidated both in vivo and in vitro.Results: FUBP1 was upregulated in 85% of KRAS mutation and 25% of wildtype CRC patients which correspondence to the metastasis rate. Further, elevated FUBP1 was positively correlated with CRC lymph node metastasis and clinical stages and negatively associated with overall survival, whatever KRAS mutation or wildtype. Overexpression of FUBP1 significantly enhanced migration, invasion, tumor sphere formation and CD133/ALDH1 expression of CRC cells in vitro and the tumorigenicity in vivo. Mechanistically, FUBP1 promoted the initiation of CSCs by activating Wnt/β-catenin signaling via directly binding to the promoter of DVL1, a vigoroso activator of β-catenin. The knockdown of DVL1 tremendously blockaded the stem-transformation and tumorigenicity of CRC. Activation of Wnt/β-catenin signaling by DVL1 increased pluripotent transcription factors, including c-Myc, NANOG, SOX2 rather c-Myc alone. Moreover, FUBP1 was upregulated at the post-transcriptional level. Elevated FUBP1 in KRAS wildtype CRC patients is due to the decrease of Smurf2, which promotes ubiquitin-mediated degradation of FUBP1. Whereas FUBP1 was upregulated in mutated KRAS patients through both inhibition of caspase-3-dependent cleavage and decreased Smurf2.Conclusions: Our results demonstrate for the first time that FUBP1 is a novel oncogene for the initiation of CSCs as a new endogenous Wnt signaling powerful agonist and may provide an important prognostic factor and therapeutic target for metastasis in both KRAS mutation and wildtype CRC.

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“…SMURF2 was shown to ubiquitinate and regulate stability, localisation, and functions of several critical proteins pertinent to cancer initiation, progression, and therapeutic response. These include TGF-β receptor and SMAD transducers 6–9 , the components of the Wnt/β-catenin signalling pathway Axin 10 and GSK3β 11 , DNA topology regulator Topo IIα 12 , epigenetic modifiers RNF20 13 , 14 , EZH2 14–16 , SIRT1 17 , transcription factors KLF5 18 , YY1 19 , SATB1 20 , ChREBP 21 , nuclear lamins 22 , 23 , as well as HECT- and RING-type E3s 24–26 . This broad target repertoire of SMURF2 suggests that modulation of its protein abundance and activity could have a profound impact on several essential molecular and cellular processes involved in the disease onset, progression, and therapeutic response.…”

Section: Introductionmentioning

confidence: 99%

Development and characterisation of SMURF2-targeting modifiers

Ayyathan

Levy-Cohen

Shubely

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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The ubiquitination ligase SMURF2 reduces aerobic glycolysis and colorectal cancer cell proliferation by promoting ChREBP ubiquitination and degradation

Cited by 29 publications

References 37 publications

SMAD-specific E3 ubiquitin ligase 2 promotes angiogenesis by facilitating PTX3 degradation in MSCs from patients with ankylosing spondylitis

SMAD-specific E3 ubiquitin ligase 2 promotes angiogenesis by facilitating PTX3 degradation in MSCs from patients with ankylosing spondylitis

FUBP1 Promotes Colorectal Cancer Stemness and Metastasis via DVL1-Mediated Activation of Wnt/β-Catenin Signaling

Development and characterisation of SMURF2-targeting modifiers

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