UCHL1 acts as a colorectal cancer oncogene via activation of the β-catenin/TCF pathway through its deubiquitinating activity

Zhong, Jialing; Zhao, Mei; Ma, Yiming; Luo, Qin; Liu, Jian; Wang, Jia; Yuan, Xinghua; Sang, Jianli; Huang, Changzhi

doi:10.3892/ijmm.2012.1012

Cited by 62 publications

(45 citation statements)

References 22 publications

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“…For example, PLAGL2 (Pleomorphic adenomas gene-like 2) and Dishevelled-2 (DVL2) have been shown to activate Wnt pathway in glioblastomas and to sustain self-renewal in glioma CSCs independently of beta-catenin mutations [23, 32]. UCHL1 has also been proposed to activate Wnt signaling through deubiquitination and stabilization of beta-catenin [33]. In this study, using TCF-dependent TOPflash reporter system we found approximately, a 70% decrease in the activity of Wnt pathway in our KDs model system, thus suggesting that Wnt or of its downstream effectors could be influencing sphere formation, cell proliferation, and/or invasion.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is associated with stem-like cancer cell functions in pediatric high-grade glioma

Sánchez-Díaz

Chang²,

Moses

et al. 2017

PLoS ONE

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Pediatric high-grade gliomas represent 8–12% of all primary tumors of the nervous system in children. Five-year survival for these pediatric aggressive tumors is poor (15–35%) indicating the need to develop better treatments for pediatric high-grade gliomas. In this work we used SF188 and SJ-GBM2 cell lines to study the function of the ubiquitin carboxyl-terminal esterase L1 (UCHL1), a deubiquitinase de-regulated in several cancers, in pediatric high-grade gliomas. UCHL1 depletion in SF188 and SJ-GBM2 glioma cells was associated with decreased cell proliferation and invasion, along with a reduced ability to grow in soft agar and to form spheres (i.e. self-renewal measure). A 70% reduction in Wnt signaling was also observed in the SF188 and SJ-GBM2 UCHL1 knockdowns (KDs) using a TCF-dependent TOPflash reporter assay. Transcriptome comparisons of UCHL1 KDs versus vector control identified a list of 306 differentially expressed genes (at least 2-fold change; p <0.05) which included genes known to be involved in cancer like ACTA2, POSTN, LIF, FBXL7, FBXW11, GDF15, HEY2, but also potential novel genes such us IGLL5, ABCA4, AQP3, AQP4, CALB1, and ALK. Bioinformatics gene ontology (GO) analysis of these 306 genes revealed significant enrichment in “signal peptides”, “extracellular matrix”and “secreted proteins” GO Terms. “Angiogenesis and blood vessel development”, “neuron differentiation/development”, cell adhesion”, and “cell migration” also showed significant enrichment in our GO analysis. Top canonical pathways identified by Ingenuity Pathway Analysis (IPA) included “Clathrin-mediated Endocytosis Signaling” (p = 5.14x10-4), “Virus Entry via Endocytic Pathways” (p = 6.15x 10−4), and “High Mobility Group-Box 1 (HMGB1) Signaling” (p = 6.15x10-4). While FGF2, IL1B, TNF and PDGFB were predicted as top upstream regulators (p < 2x10-16) of the UCHL1 KD-associated transcriptome. Aberrant expression of UCHL1 in pediatric high-grade gliomas may promote cell invasion, transformation, and self-renewal properties, at least in part, by modulating Wnt/Beta catenin activity. UCHL1 might act as an oncogene in glioma within the gene network that imparts stem-like characteristics to these cancer cells.

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Section: Discussionmentioning

confidence: 99%

Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is associated with stem-like cancer cell functions in pediatric high-grade glioma

Sánchez-Díaz

Chang²,

Moses

et al. 2017

PLoS ONE

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“…Expression plasmids pcDNA3.1/UCHL1 and pcDNA3.1/ UCHL1-C90S were kindly provided by Dr. Jialing Zhong [10]. Lentiviral vector pLVX-Puro was kindly provided by Sheng-kai Huang.…”

Section: Plasmid Constructionmentioning

confidence: 99%

“…Xiang et al have reported that UCHL1 induces G0/G1 cell cycle arrest and apoptosis through stabilizing p53 in breast cancer [6]. On the other hand, UCHL1 is also considered as an oncogene in cancers including non-small lung cancer, lymphoma, prostate cancer, colorectal cancer, melanoma, as well as osteosarcoma [7][8][9][10][11][12]. Meanwhile, Lien et al also demonstrated that high expression of UCHL1 in metaplastic carcinomas of the breast is related to epithelial-mesenchymal transition (EMT) [13].…”

Section: Introductionmentioning

confidence: 99%

The de-ubiquitinase UCHL1 promotes gastric cancer metastasis via the Akt and Erk1/2 pathways

Yang

Zhao

et al. 2015

Tumor Biol.

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Ubiquitin C-terminal hydrolase-L1 (UCHL1) is a de-ubiquitinating enzyme, which enzymatic activity relies on the C90 site. The function of UCHL1 is controversial in different types of cancer, and its role in gastric cancer progression remains unclear. In this study, immunohistochemistry staining was applied to detect the expression of UCHL1 in primary gastric cancer and liver metastases from gastric cancer. MKN45 and BGC823 cell lines with stable expression of de-ubiquitinase active UCHL1 or inactive UCHL1-variant C90S were established by lentiviral infection. The effect of UCHL1 on cell proliferation was evaluated by MTT and colony formation assays. The abilities of cell migration and invasion were determined by transwell assay. Protein expression levels were determined by Western blot. The results indicated that UCHL1 had a significantly higher positive expression rate in liver metastases from gastric cancer compared with primary gastric cancer. Overexpression of UCHL1 in MKN45 and BGC823 cells promoted cell proliferation, migration, and invasion depending on its de-ubiquitinase activity. UCHL1 activated Akt and Erk1/2, which process also required enzymatic activity and was necessary for mediating cell migration and invasion. These findings demonstrated that UCHL1 promoted cell proliferation, migration, and invasion depending on its de-ubiquitinase activity by activating Akt and Erk1/2, which may account for its higher positive expression rate in liver metastases from gastric cancer. UCHL1 could be a candidate biomarker and a therapeutic target for gastric cancer metastasis.

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“…UCHL1 is highly expressed in non-small lung cancer cell line H157 and promotes invasion via activating the upstream Akt [19]. UCHL1 also acts as a colorectal cancer oncogene via activation of the beta-catenin/TCF pathway through its deubiquitinating activity [20]. Recently, UCHL1 is reported to promote metastases as a deubiquitinating enzyme for HIF-1␣ [21].…”

Section: Verification Of Differentially Expressed Proteins By Rt-pcrmentioning

confidence: 99%

Proteomic analysis of β-asarone induced cytotoxicity in human glioblastoma U251 cells

Chen

Ning

et al. 2015

Journal of Pharmaceutical and Biomedical Analysis

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UCHL1 acts as a colorectal cancer oncogene via activation of the β-catenin/TCF pathway through its deubiquitinating activity

Cited by 62 publications

References 22 publications

Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is associated with stem-like cancer cell functions in pediatric high-grade glioma

Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is associated with stem-like cancer cell functions in pediatric high-grade glioma

The de-ubiquitinase UCHL1 promotes gastric cancer metastasis via the Akt and Erk1/2 pathways

Proteomic analysis of β-asarone induced cytotoxicity in human glioblastoma U251 cells

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