TRIM21 mediates ubiquitination of Snail and modulates epithelial to mesenchymal transition in breast cancer cells

Jin, Yue; Zhang, Yu; Boyuan, Li; Zhang, Jing; Zhang, Dong; Hu, Xin; Wan, Yong

doi:10.1016/j.ijbiomac.2018.11.269

Cited by 51 publications

(34 citation statements)

References 30 publications

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“…According to Jin Y. 46 , TRIM21 could interact with Snail, a master regulator of EMT, and lead to increased ubiquitination degradation of Snail in breast cancer cells MCF-7 and T-47D, these evidences are consistent with us that TRIM21 is a potential tumor suppressor in breast cancer. Strikingly, we identified that SET7/9 was another substrate of TRIM21, by mediating the proteosomal degradation of SET7/9, TRIM21 could suppress the proliferation, migration, and invasion of breast cancer cells.…”

Section: Discussionsupporting

confidence: 73%

SET7/9 promotes multiple malignant processes in breast cancer development via RUNX2 activation and is negatively regulated by TRIM21

Zhou

Zhao

et al. 2020

Cell Death Dis

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Although the deregulation of lysine methyltransferase (su(var)-3-9, enhancer-of-zeste, trithorax) domain-containing protein 7/9 (SET7/9) has been identified in a variety of cancers, the potential role of SET7/9 and the molecular events in which it is involved in breast cancer remain obscure. Using the online Human Protein Atlas and GEO databases, the expression of SET7/9 was analyzed. Furthermore, we investigated the underlying mechanisms using chromatin immunoprecipitation-based deep sequencing (ChIP-seq) and quantitative ChIP assays. To explore the physiological role of SET7/9, functional analyses such as CCK-8, colony formation, and transwell assays were performed and a xenograft tumor model was generated with the human breast cancer cell lines MCF-7 and MDA-MB-231. Mass spectrometry, co-immunoprecipitation, GST pull-down, and ubiquitination assays were used to explore the mechanisms of SET7/9 function in breast cancer. We evaluated the expression of SET7/9 in different breast cancer cohorts and found that higher expression indicated worse survival times in these public databases. We demonstrated positive effects of SET7/9 on cell proliferation, migration, and invasion via the activation of Runt-related transcription factor 2 (RUNX2). We demonstrate that tripartite motif-containing protein 21 (TRIM21) physically associates with SET7/9 and functions as a major negative regulator upstream of SET7/9 through a proteasome-dependent mechanism and increased ubiquitination. Taken together, our data suggest that SET7/9 has a promoting role via the regulation of RUNX2, whereas TRIM21-mediated SET7/9 degradation acts as an anti-braking system in the progression of breast cancer.

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Section: Discussionsupporting

confidence: 73%

SET7/9 promotes multiple malignant processes in breast cancer development via RUNX2 activation and is negatively regulated by TRIM21

Zhou

Zhao

et al. 2020

Cell Death Dis

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“…It is found to decrease proliferation, colony formation and migration of hepatocellular carcinoma cells 23 . It also degrades snail, thereby preventing the epithelial to mesenchymal transition in breast cancer cells, one of the hallmarks of cancer 24 , 39 . Moreover, TRIM21 degrades anti-apoptotic molecule, Bcl2, thereby triggering apoptosis in cervical cancer cells 40 .…”

Section: Discussionmentioning

confidence: 99%

“…It has been found to be downregulated in many liver cancer patients 23 . Moreover, TRIM21 is involved in the epithelial to mesenchymal transition in breast cancer cells 24 . TRIM21 also promotes the proliferation of osteosarcoma cells and its expression enhances the tolerance of osteosarcoma cells to various stresses 25 .…”

Section: Introductionmentioning

confidence: 99%

Negative feedback regulation by HuR controls TRIM21 expression and function in response to UV radiation

Guha

Nag

Ray

2020

Sci Rep

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The E3 ubiquitin ligase TRIM21 plays a crucial role as a negative regulator of innate immune responses. Recent evidence has also indicated the involvement of TRIM21 in the genotoxic stress response and suppressing tumorigenesis. Our previous work has demonstrated a new function of TRIM21 in inhibiting p53 protein synthesis by degrading the RNA-binding protein HuR in response to UV radiation. This suggested a pro-oncogenic role of TRIM21. In this study, we have shown that TRIM21 enhances the proliferation of MCF7 breast carcinoma cells and counteracts the decrease in cell proliferation and colony formation caused by UV-induced DNA damage. Further, this pro-oncogenic role of TRIM21 in response to DNA damage is mediated by its degradation of HuR. Conversely, we found that HuR binds to a U-rich element in the 3′UTR of TRIM21 mRNA and activates its translation, thereby constituting a negative feedback loop. We found that dihydrotanshinone-I (DHTS-I), a plantderived product which prevents HuR binding to specific RNAs, prevented HuR-mediated upregulation of TRIM21, while increasing the HuR-mediated upregulation of p53. Together, these findings demonstrate a negative feedback regulation between TRIM21 and HuR, which may play an important role in regulating the level of p53 in the genotoxic stress response. TRIM (Tripartite motif) family proteins are ubiquitously found in all metazoans and are recognized for conserved biological functions, such as control of cell proliferation and differentiation. However, with the appearance of complex immune systems in jawed vertebrates, some of these have evolved to directly regulate antiviral action and cytokine production. TRIM family proteins are primarily recognized as post-translational modifiers. Nevertheless, some of the members of this family are implicated in RNA metabolism. These TRIM proteins are specifically localized in the cytoplasmic processing bodies. Furthermore, about half of all the TRIM family proteins are involved in autophagy. Most of these are also involved in the formation of TRIMosomes which are considered to facilitate autophagic engulfment and subsequent lysosomal degradation 1. E3 ubiquitin ligase TRIM21 is a 52 kDa protein belonging to the TRIM family. Similar to many other TRIM family proteins, TRIM21 has a characteristic N-terminal RING domain, B-box domain, coiled-coil domain (collectively called RBCC). The RING domain is implicated in E3 ubiquitin ligase activity, whereas the B-box domain has been shown to be a negative regulator of RING domain. Recently, the phosphorylation of serine-80 (S80) or phosphomimetic serine-80 to glutamate (S80E) mutation in TRIM21 has been found to release the inhibition of B-box domain 2,3. The coiled-coil domain is utilized in homo-dimerization of TRIM21 which ensures binding with the substrate in a stoichiometry of 2:1 2. TRIM21 has also C-terminal PRYSPRY domain which is required for target protein recognition. Structural analysis of PRYSPRY domain of TRIM21 has demonstrated its diverse functions. Isothermal titration ca...

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“…We have also shown that endoglin can interact with TRIM21, a protein involved in multiple cell functions. As other members of the TRIM family, TRIM21 can act as a ubiquitination enzyme targeting for degradation different proteins [56,57,58,90]. The TRIM family has been shown to ubiquitinate different components of the TGF-β signaling pathway [55,91], and our results suggest for the first time that TRIM21 may target for degradation the TGF-β auxiliary receptor endoglin.…”

Section: Discussionmentioning

confidence: 63%

“…Unfortunately, little is known about the connection between the TRIM family and the TGF-β auxiliary receptor endoglin of endothelial cells. Among TRIM family members, TRIM21 acts not only as an E3 ubiquitin ligase on different target proteins, but also as a substrate in auto-ubiquitination, both leading to protein degradation [56,57,58]. In addition, TRIM21 is involved in cancer [59,60], inflammation [61,62,63,64], intracellular immunity, and autoimmunity [47,65,66,67].…”

Section: Resultsmentioning

confidence: 99%

Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners

Gallardo-Vara

Ruíz-Llorente

Casado‐Vela

et al. 2019

Cells

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Endoglin is a 180-kDa glycoprotein receptor primarily expressed by the vascular endothelium and involved in cardiovascular disease and cancer. Heterozygous mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1, a vascular disease that presents with nasal and gastrointestinal bleeding, skin and mucosa telangiectases, and arteriovenous malformations in internal organs. A circulating form of endoglin (alias soluble endoglin, sEng), proteolytically released from the membrane-bound protein, has been observed in several inflammation-related pathological conditions and appears to contribute to endothelial dysfunction and cancer development through unknown mechanisms. Membrane-bound endoglin is an auxiliary component of the TGF-β receptor complex and the extracellular region of endoglin has been shown to interact with types I and II TGF-β receptors, as well as with BMP9 and BMP10 ligands, both members of the TGF-β family. To search for novel protein interactors, we screened a microarray containing over 9000 unique human proteins using recombinant sEng as bait. We find that sEng binds with high affinity, at least, to 22 new proteins. Among these, we validated the interaction of endoglin with galectin-3, a secreted member of the lectin family with capacity to bind membrane glycoproteins, and with tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase. Using human endothelial cells and Chinese hamster ovary cells, we showed that endoglin co-immunoprecipitates and co-localizes with galectin-3 or TRIM21. These results open new research avenues on endoglin function and regulation.

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TRIM21 mediates ubiquitination of Snail and modulates epithelial to mesenchymal transition in breast cancer cells

Cited by 51 publications

References 30 publications

SET7/9 promotes multiple malignant processes in breast cancer development via RUNX2 activation and is negatively regulated by TRIM21

SET7/9 promotes multiple malignant processes in breast cancer development via RUNX2 activation and is negatively regulated by TRIM21

Negative feedback regulation by HuR controls TRIM21 expression and function in response to UV radiation

Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners

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