Sal-like 4 protein levels in breast cancer cells are post-translationally down-regulated by tripartite motif–containing 21

Itou, Junji; Li, Wenzhao; Ito, Shinji; Tanaka, Sunao; Matsumoto, Yoshiaki; Sato, Fumiaki; Toi, Masakazu

doi:10.1074/jbc.ra117.000245

Cited by 22 publications

(15 citation statements)

References 29 publications

(1 reference statement)

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“…S100A10, a small dimeric helix-loop-helix protein residing in a tight complex with Annexin A2, appeared to regulate the intracellular trafficking of a variety of membrane-resident proteins, such as cathepsin B (38). TRIM21 is an E3 ubiquitin ligase associated with autoimmune diseases (39), and the dysregulation of TRIM21 facilitates human cancer development (40,41). This study detected a significant decrease of TRIM21 and Annexin A2 levels in PGCCs with their daughter cells after S100A4 knockdown as well as a reduced nuclear translocation of S100A10 in daughter cells, while 14-3-3 ζ/δ and Ezrin did not vary.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Fei

et al. 2020

Front. Oncol.

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Recently, an increasing number of evidences have shown that polyploid giant cancer cells (PGCCs) could generate daughter cells with a strong migration and invasion ability, which have been implicated in cancer recurrence and metastasis. However, the underlying molecular mechanisms of PGCCs with their daughter cells remain largely unclear. In vitro and in vivo experiments combined with 222 cases of human colorectal cancer (CRC) samples were used to identify the molecular mechanisms of S100A4-related proteins regulating the invasion and metastasis of PGCCs with their daughter cells. PGCCs with their daughter cells had high migration, invasion, and proliferation abilities compared to control cells; these were significantly inhibited after S100A4 knockdown. The high expression of cathepsin B, cyclin B1, TRIM21, and Annexin A2 were significantly downregulated after S100A4 knockdown, while the overexpression of S100A4, cathepsin B, cyclin B1, and S100A10 were significantly downregulated after TRIM21 knockdown in PGCCs with their daughter cells. The tumorigenic and metastatic ability of PGCCs with their daughter cells in vivo was significantly stronger compared to the untreated cells, which was significantly decreased after S100A4 knockdown. Moreover, the expression of S100A4-related proteins was positively correlated with the malignancy degree of human CRC, and maintained a high level in lymph node metastasis. S100A4 and TRIM21 may regulate each other to affect the expression and subcellular localization of cyclin B1, and participate in regulating the structure and function of Annexin A2/S100A10 complex, affecting downstream cathepsin B, resulting in the invasion and metastasis of PGCCs with their daughter cells. Besides, 14-3-3 ζ/δ and Ezrin may be involved in the motility and invasion of PGCCs with their daughter cells via cytoskeletal constructions with S100A4.

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Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Fei

et al. 2020

Front. Oncol.

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“…First, TRIM21 was capable of ubiquitylating and degrading oncoproteins involved in the maintenance of cell stemness, such as SALL4 and OCT1. 10 , 12 Second, TRIM21 was able to affect the progression of the cell cycle, autophagy, and apoptosis via modulating expression of p53, SQSTM1/p62, and Par-4. 11 , 24 , 25 Third, TRIM21 is involved in the regulation of glycolysis and DNA repair by downregulating DDX41 and phosphofructokinase 1 platelet isoform.…”

Section: Discussionmentioning

confidence: 99%

“… 11 In breast cancer, TRIM21 was found to be capable of downregulating the expression of Sal-like 4 (SALL4) and Lifeguard. 12 , 13 However, the clinical significance of TRIM21 and its role in cell proliferation in breast cancer remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Decreased expression of TRIM21 indicates unfavorable outcome and promotes cell growth in breast cancer

Zhou

Zhang

Zhong

et al. 2018

CMAR

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BackgroundTripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase, has been implicated in autoimmune diseases. Dysregulation of TRIM21 contributes to the progression of human malignancies, but its role and clinical significance in breast cancer remain unclear.MethodsThe expression of TRIM21 was examined by quantitative real-time PCR, Western blot, and immunohistochemistry. The role of TRIM21 in the progression of breast cancer was determined using in vitro and in vivo models. The upstream regulation of TRIM21 was investigated by luciferase reporter assay.ResultsHere, we showed that TRIM21 expression in breast cancer tissues was decreased at both the mRNA and protein levels in comparison to that in nontumorous tissues. TRIM21 expression was closely associated with tumor size, estrogen receptor, human epidermal growth factor receptor 2, and clinical stage. Low TRIM21 expression was correlated with poor overall and disease-free survival in two independent cohorts containing 1,219 patients with breast cancer. A multivariate Cox regression model suggested TRIM21 as an independent factor for overall survival. In vitro data revealed that TRIM21 expression was suppressed by miR-494-3p directly targeting the 3′ untranslated region of TRIM21. Overexpression of TRIM21 impeded cell proliferation and tumor growth in breast cancer, whereas TRIM21 depletion enhanced these capacities.ConclusionCollectively, our findings indicate that TRIM21 serves as a potential prognostic biomarker and functions as a tumor suppressor in breast cancer.

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“…TRIM21 is a multifunctional protein and its role as an intracellular antibody receptor in immune responses has been extensively studied. As an E3 ligase, TRIM21 targets several substrates involved in innate and adaptive immunity and cancer development, including sequestosome 1 (SQSTM1/p62) ( 39 ), mitochondrial antiviral signaling protein ( 40 ), and multiple members of the interferon regulation factor (IRF) protein family (IRF3/5/7/8) ( 41 , 42 , 43 , 44 ). Our study has identified ion channels as a target of TRIM21 E3 ligase for the first time.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, decreased TRIM21 protein and mRNA expression has also been linked to several cancers. For example, TRIM21 suppresses colorectal and breast cancers by ubiquitinating and causing the degradation of, respectively, serine hydroxymethyltransferase 2 ( 44 ) and the transcription factors Sal-like proteins 1 and 4 ( 42 ); moreover, TRIM21 downregulation in breast cancer is closely correlated with the large tumor size and poor prognosis ( 54 ). Conversely, elevated TRIM23 expression has been suggested to be associated with poor prognosis in gastric cancer ( 55 ) and HNSCC ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

Opposing roles of E3 ligases TRIM23 and TRIM21 in regulation of ion channel ANO1 protein levels

Cao

Zhou

Tian

et al. 2021

Journal of Biological Chemistry

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Sal-like 4 protein levels in breast cancer cells are post-translationally down-regulated by tripartite motif–containing 21

Abstract: Keywords:On the list: breast cancer, E3 ubiquitin ligase, molecular biology, protein degradation, transcription factor Not on the list: Ro52, SALL family, SALL4, TRIM21 http://www.jbc.org/cgi

Cited by 22 publications

References 29 publications

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Decreased expression of TRIM21 indicates unfavorable outcome and promotes cell growth in breast cancer

Opposing roles of E3 ligases TRIM23 and TRIM21 in regulation of ion channel ANO1 protein levels

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