TRAF6 regulates melanoma invasion and metastasis through ubiquitination of Basigin

Luo, Zhu; Zhang, Xu; Zeng, Weiqi; Su, Juan; Yang, Keda; Lü, Lixia; Lim, Chuan Bian; Tang, Wen; Wu, Lisha; Zhao, Shuang; Jia, Xuekun; Peng, Cong; Chen, Xiang

doi:10.18632/oncotarget.6886

Cited by 49 publications

(74 citation statements)

References 40 publications

(42 reference statements)

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“…In this study, we found that EGCG significantly attenuated the proliferation and metastasis of melanoma (Figure 5), a finding that is consistent with the results of our previous study concerning the effects of TRAF6 in melanoma [23]. NF-κB is member of a family of proteins including RelA (p65), RelB and c-Rel [61] that form homo- or heterodimers and bind to specific sequences in promoter regions in response to extracellular stimuli, such as inflammation, cytokines, and tumor promoters.…”

Section: Discussionsupporting

confidence: 92%

Epigallocatechin-3-gallate(EGCG) suppresses melanoma cell growth and metastasis by targeting TRAF6 activity

et al. 2016

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TRAF6 (TNF Receptor-Associated Factor 6) is an E3 ubiquitin ligase that contains a Ring domain, induces K63-linked polyubiquitination, and plays a critical role in signaling transduction. Our previous results demonstrated that TRAF6 is overexpressed in melanoma and that TRAF6 knockdown dramatically attenuates tumor cell growth and metastasis. In this study, we found that EGCG can directly bind to TRAF6, and a computational model of the interaction between EGCG and TRAF6 revealed that EGCG probably interacts with TRAF6 at the residues of Gln54, Gly55, Asp57 ILe72, Cys73 and Lys96. Among these amino acids, mutation of Gln54, Asp57, ILe72 in TRAF6 could destroy EGCG bound to TRAF6, furthermore, our results demonstrated that EGCG significantly attenuates interaction between TRAF6 and UBC13(E2) and suppresses TRAF6 E3 ubiquitin ligase activity in vivo and in vitro. Additionally, the phosphorylation of IκBα, p-TAK1 expression are decreased and the nuclear translocation of p65 and p50 is blocked by treatment with EGCG, leading to inactivation of the NF-κB pathway. Moreover, EGCG significantly inhibits cell growth as well as the migration and invasion of melanoma cells. Taken together, these findings show that EGCG is a novel E3 ubiquitin ligase inhibitor that could be used to target TRAF6 for chemotherapy or the prevention of melanoma.

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Section: Discussionsupporting

confidence: 92%

Epigallocatechin-3-gallate(EGCG) suppresses melanoma cell growth and metastasis by targeting TRAF6 activity

et al. 2016

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“…Al‐Azayzih observed that stimulation with TGFβ1 induced prostate tumour cell scattering and increased expression of Snail and N‐cadherin through TRAF6‐mediated activation of Rac1/Pak1 pathway . TRAF6 knockdown can significantly decrease invasion and metastasis abilities in melanomas and lung cancer . In the present study, we found that TRAF6 was highly expressed in SCCHN cell lines.…”

Section: Discussionsupporting

confidence: 62%

TRAF6 regulates tumour metastasis through EMT and CSC phenotypes in head and neck squamous cell carcinoma

Chen

et al. 2017

J Cellular Molecular Medi

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Epithelial–mesenchymal transition (EMT) is associated with metastasis formation, generation and maintenance of cancer stem cells (CSCs). However, the regulatory mechanisms of CSCs have not been clarified. This study aims to investigate the role of TNF receptor‐associated factor 6 (TRAF6) on EMT and CSC regulation in squamous cell carcinoma of head and neck (SCCHN). We found TRAF6 was overexpressed in human SCCHN tissues, and high TRAF6 expression was associated with lymphatic metastasis and resulted in poor prognosis in patients with SCCHN. In addition, elevated TRAF6 expression was observed in several HNSCC cell lines, and wound healing and transwell assay results showed that TRAF6 knockdown inhibited the migration and invasion ability of the SCCHN cells. Moreover, the expression of Vimentin, Slug and N‐cadherin was down‐regulated and that of E‐cadherin was elevated after TRAF6 knockdown but decreased by transforming growth factor beta 1 (TGF‐β1) and CAL27 similar to mesenchymal cells formed after TGF‐β1 induction. In addition, the expression levels of CD44, ALDH1, KLF4 and SOX2 were inhibited after TRAF6 knockdown, and the anchor‐dependent colony formation number and sphere number were remarkably reduced. Flow cytometry showed TRAF6 knockdown reduced ALDH1‐positive cancer stem cells. We also demonstrated that TRAF6 is closely associated with EMT process and cancer stem cells using a Tgfbr1/Pten 2cKO mice SCCHN model and human SCCHN tissue microarray. Our findings indicate that TRAF6 plays a role in EMT phenotypes, the generation and maintenance of CSCs in SCCHN, suggesting that TRAF6 is a potential therapeutic target for SCCHN.

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“…The TM domain of Basigin consists of a stretch of ≈23 highly hydrophobic residues, which are found to be highly conserved among species . Basigin is a TM protein, but it is also known to be localized in the cytoplasm and mitochondria . Basigin encourages MMP over‐expression in tumor cells by stimulating adjacent fibroblasts and regulates cancer progression .…”

Section: Introductionmentioning

confidence: 99%

“…Ubiquitin is transferred from E2 to the substrate, and the substrate is either marked for degradation or localization. It mediates K‐63 linked ubiquitin tagging of substrates . It is known to be involved in many cellular pathways by interacting with the intercellular domains of many receptors.…”

Section: Introductionmentioning

confidence: 99%

“…Luo et al demonstrated the membrane localization and activation of Basigin by K‐63 mediated ubiquitination in melanoma cells. The in vitro experiments using human melanoma cell lines SK‐MEL‐5 and SK‐MEL‐28 indicated a higher expression level of TRAF6 in melanoma cells and the involvement of TRAF6 in melanoma spread, which was further confirmed by in vivo studies using xeno‐transplantation that is the grafting of human cancer cells in animal system . Mouse models are known to be very effective in replicating human systems.…”

Section: Introductionmentioning

confidence: 99%

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A structural perspective on the interactions of TRAF6 and Basigin during the onset of melanoma: A molecular dynamics simulation study

Biswas

Ghosh

Bagchi

2017

J of Molecular Recognition

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Metastatic melanoma is the most fatal type of skin cancer. The roles of matrix metalloproteinases (MMPs) have well been established in the onset of melanoma. Basigin (BSG) belongs to the immunoglobulin superfamily and is critical for induction of extracellular MMPs during the onset of various cancers including melanoma. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3-ligase that interacts with BSG and mediates its membrane localization, which leads to MMP expression in melanoma cells. This makes TRAF6 a potential therapeutic target in melanoma. We here conducted protein-protein interaction studies on TRAF6 and BSG to get molecular level insights of the reactions. The structure of human BSG was constructed by protein threading. Molecular-docking method was applied to develop the TRAF6-BSG complex. The refined docked complex was further optimized by molecular dynamics simulations. Results from binding free energy, surface properties, and electrostatic interaction analysis indicate that Lys340 and Glu417 of TRAF6 play as the anchor residues in the protein interaction interface. The current study will be helpful in designing specific modulators of TRAF6 to control melanoma metastasis.

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TRAF6 regulates melanoma invasion and metastasis through ubiquitination of Basigin

Cited by 49 publications

References 40 publications

Epigallocatechin-3-gallate(EGCG) suppresses melanoma cell growth and metastasis by targeting TRAF6 activity

Epigallocatechin-3-gallate(EGCG) suppresses melanoma cell growth and metastasis by targeting TRAF6 activity

TRAF6 regulates tumour metastasis through EMT and CSC phenotypes in head and neck squamous cell carcinoma

A structural perspective on the interactions of TRAF6 and Basigin during the onset of melanoma: A molecular dynamics simulation study

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