TRIM66 confers tumorigenicity of hepatocellular carcinoma cells by regulating GSK-3β-dependent Wnt/β-catenin signaling

Fan, Wanhu; Du, Fenjing; Liu, Xiaojing

doi:10.1016/j.ejphar.2019.01.054

Cited by 25 publications

(18 citation statements)

References 39 publications

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“… 16 TRIM66 expression is upregulated in hepatocellular carcinoma and confers tumorigenicity by regulating GSK3 Wnt signaling. 8 TRIM66 is overexpressed in NSCLC patients and serves as a prognostic marker. 17 Knockdown of TRIM66 inhibits malignant behavior and epithelial–mesenchymal transition in NSCLC cells.…”

Section: Discussionmentioning

confidence: 99%

“…In hepatocellular carcinoma (HCC), overexpression of TRIM66 promoted cell proliferation and invasion. 8 TRIM66 activated Wnt signaling by increasing glycogen synthase kinase-3β (GSK-3β) phosphorylation and β-catenin expression. 8 TRIM66 deficiency suppressed cell viability, proliferation, migration, and invasion in prostate cancer cells, possibly through regulation of STAT2/IL-2 signaling.…”

Section: Introductionmentioning

confidence: 99%

“… 8 TRIM66 activated Wnt signaling by increasing glycogen synthase kinase-3β (GSK-3β) phosphorylation and β-catenin expression. 8 TRIM66 deficiency suppressed cell viability, proliferation, migration, and invasion in prostate cancer cells, possibly through regulation of STAT2/IL-2 signaling. 9 These studies indicated that TRIM66 might function as an oncogenic protein.…”

Section: Introductionmentioning

confidence: 99%

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TRIM66 Overexpression Promotes Glioma Progression and Regulates Glucose Uptake Through cMyc/GLUT3 Signaling

Song

Meng

et al. 2021

CMAR

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Objective Tripartite motif 66 (TRIM66) is reported to be closely associated with human cancers. However, the roles of TRIM66 in glioma remain unclear. The present study aimed to investigate the clinical significance and biological roles of TRIM66 in human glioma. Methods TRIM66 expression in glioma tissues was examined by immunohistochemistry. TRIM66 overexpression and siRNA knockdown were performed in glioblastoma cell lines. CCK8, colony formation assay, transwell assay, Annexin V and JC1 staining, glucose uptake assay, and Western blotting were used to explore the biological roles and potential underlying mechanisms of TRIM66 in glioma progression. Results Our results showed that TRIM66 was overexpressed in 52/95 glioma cases. The rates of TRIM66 overexpression in Grade I, Grade II, Grade III, and Grade IV gliomas were 16.6%, 41.3%, 58.6%, and 70.9%, respectively. Oncomine data showed that TRIM66 was upregulated in glioblastoma and oligodendroglioma compared with normal brain tissues. TRIM66 expression was higher in glioblastoma cell lines compared with normal SVG p12 glial cell line. TRIM66 promoted in vitro and in vivo proliferation, invasion, and inhibited temozolomide (TMZ)-induced apoptosis. Notably, TRIM66 increased glucose metabolism by upregulating glucose uptake, glucose consumption, and ATP production. Western blotting showed that TRIM66 positively regulated cMyc and GLUT3. Depletion of cMyc by siRNA abolished the effect of TRIM66 on GLUT3. Chromatin immunoprecipitation (ChIP) assay showed that cMyc could bind to the promoter regions of GLUT3 in glioblastoma cells. Conclusion TRIM66 was upregulated in human gliomas, where it promoted cell growth and chemoresistance. Our data also identified novel roles of TRIM66 in glioma progression. TRIM66 upregulates glucose uptake and mitochondrial function through the cMyc/GLUT3 signaling, which makes it a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TRIM66 Overexpression Promotes Glioma Progression and Regulates Glucose Uptake Through cMyc/GLUT3 Signaling

Song

Meng

et al. 2021

CMAR

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“…Apart from ALK, we found seven genes (Tha1, Trim66, Gzma, Socs3, Gm5611, 5830468F06Rik, and Gm17910), which were up-regulated both in ALK and ALKKO cells compared with Ctrl. These include the suppressor of cytokine signaling 3 (Socs3), which is a regulator of the JAK/STAT signaling pathway and was also found up-regulated in human ALK+ ALCL cell lines (54), tripartite motif containing 66 (Trim66), which is part of the rat sarcoma (RAS) pathway that regulates DNMT1 expression and is known to promote proliferation (55,56,57) and granzyme A (Gzma) a canonical cytotoxic gene that is involved in cancer initiation and progression (58) (Fig 5D). In addition, strong up-regulation of c-Myc, Cdk4/6, and Cyclin D1 was detectable in ALK tumors at the RNA level, which was in concordance with elevated protein levels of these cell cycle regulators (Fig S6D).…”

Section: Dnmt1 Knockout Inhibits Alk-dependent Transcription Programsmentioning

confidence: 99%

Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK–driven lymphomagenesis

et al. 2020

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Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T-cell–specific lymphoma model based on the human oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK-positive tumors show a loss of associated methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis.

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“…A further RING-less TRIM protein that controls p53 abundance is TRIM66, also known as transcription intermediate factor 1 delta. Overexpression of TRIM66 was found in hepatocarcinoma, in osteosarcoma and in non-small cell lung cancer, where it is associated with metastasis, chemoresistance and poor survival [81,90,91]. Its downregulation increases the abundance of p53 and the apoptosis markers caspase 7 and caspase 9, but the mechanism by which this regulation is exerted is still unknown, albeit TRIM66 bromo-domain being possibly involved [81].…”

Section: Trim Proteins As Chemosensitizersmentioning

confidence: 99%

Targeting Chemoresistant Tumors: Could TRIM Proteins-p53 Axis Be a Possible Answer?

Valletti

Marzano

Pesole

et al. 2019

IJMS

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Chemosensitivity is a crucial feature for all tumours so that they can be successfully treated, but the huge heterogeneity of these diseases, to be intended both inter- and intra-tumour, makes it a hard-to-win battle. Indeed, this genotypic and phenotypic variety, together with the adaptability of tumours, results in a plethora of chemoresistance acquisition mechanisms strongly affecting the effectiveness of treatments at different levels. Tripartite motif (TRIM) proteins are shown to be involved in some of these mechanisms thanks to their E3-ubiquitin ligase activity, but also to other activities they can exert in several cellular pathways. Undoubtedly, the ability to regulate the stability and activity of the p53 tumour suppressor protein, shared by many of the TRIMs, represents the preeminent link between this protein family and chemoresistance. Indeed, they can modulate p53 degradation, localization and subset of transactivated target genes, shifting the cellular response towards a cytoprotective or cytotoxic reaction to whatever damage induced by therapy, sometimes in a cellular-dependent way. The involvement in other chemoresistance acquisition mechanisms, independent by p53, is known, affecting pivotal processes like PI3K/Akt/NF-κB signalling transduction or Wnt/beta catenin pathway, to name a few. Hence, the inhibition or the enhancement of TRIM proteins functionality could be worth investigating to better understand chemoresistance and as a strategy to increase effectiveness of anticancer therapies.

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TRIM66 confers tumorigenicity of hepatocellular carcinoma cells by regulating GSK-3β-dependent Wnt/β-catenin signaling

Cited by 25 publications

References 39 publications

TRIM66 Overexpression Promotes Glioma Progression and Regulates Glucose Uptake Through cMyc/GLUT3 Signaling

TRIM66 Overexpression Promotes Glioma Progression and Regulates Glucose Uptake Through cMyc/GLUT3 Signaling

Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK–driven lymphomagenesis

Targeting Chemoresistant Tumors: Could TRIM Proteins-p53 Axis Be a Possible Answer?

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