The ETV6-MECOM fusion protein promotes EMT-related properties by repressing the transactivation activity of E-cadherin promoter in K562 leukemia cells
The ETV6-MECOM fusion gene, produced by the rare and recurrent chromosomal translocation t(3; 12) (q26; p13), is associated with high mortality and short survival in myeloid leukemia. However, its function and underlying mechanisms in leukemia progression remain unknown. In this study, leukemia-stab...
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| Format: | Article |
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Elsevier
2024-07-01
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| Series: | Biochemistry and Biophysics Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580824000311 |
| _version_ | 1797302476920061952 |
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| author | Qian Li Furong Wang Xuehong Zhang Shuqing Liu Ming-Zhong Sun Jinsong Yan |
| author_facet | Qian Li Furong Wang Xuehong Zhang Shuqing Liu Ming-Zhong Sun Jinsong Yan |
| author_sort | Qian Li |
| collection | DOAJ |
| description | The ETV6-MECOM fusion gene, produced by the rare and recurrent chromosomal translocation t(3; 12) (q26; p13), is associated with high mortality and short survival in myeloid leukemia. However, its function and underlying mechanisms in leukemia progression remain unknown. In this study, leukemia-stable K562 cells expressing the ETV6-MECOM fusion protein were used to investigate the effects of the ETV6-MECOM oncoprotein. K562-ETV6-MECOM cells were undifferentiated and had reduced colony formation, increased cell migration and invasion, and increased sphere number and diameter in a spheroid formation assay, presenting epithelial-to-mesenchymal transition (EMT) traits. The expression of E-cadherin, a hallmark of EMT, was significantly downregulated at the transcriptional and translational level in K562-ETV6-MECOM cells to explore the mechanistic basis of EMT. Stepwise truncation, DNA sequence deletion, mutation analysis for E-cadherin promoter transactivation, and a dual luciferase assay indicated that the regulatory region of ETV6-MECOM is located in the DNA motif −1116 TTAAAA−1111 of E-cadherin promoter. Moreover, a chromatin immunoprecipitation assay showed that this oncoprotein binds to the DNA motif −1116 TTAAAA−1111 with the anti-EVI1 antibody. Although ETV6-MECOM upregulated the expressions of EMT master regulators, including SNAIL, SLUG, ZEB2, and TWIST2, their knockdown had no effect on EMT-related properties. However, overexpression of E-cadherin eliminated EMT traits in the presence of the ETV6-MECOM oncoprotein. These data confirmed that the ETV6-MECOM oncoprotein, not SNAIL, SLUG, ZEB2, or TWIST2, plays a critical role in inducing EMT traits in leukemia K562 cells. ETV6-MECOM induces EMT-related properties by downregulating the transcriptional expression of E-cadherin and repressing its transactivation activity by binding to its core motif −1116TTAAAA−1111 in leukemia K562 cells. These findings could contribute to the development of a therapeutic target for patients with myeloid leukemia characterized by ETV6-MECOM. |
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| id | doaj.art-73dd715c4edd49b698d3f7c9f902fba2 |
| institution | Directory Open Access Journal |
| issn | 2405-5808 |
| language | English |
| last_indexed | 2024-03-07T23:38:20Z |
| publishDate | 2024-07-01 |
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| series | Biochemistry and Biophysics Reports |
| spelling | doaj.art-73dd715c4edd49b698d3f7c9f902fba22024-02-20T04:19:23ZengElsevierBiochemistry and Biophysics Reports2405-58082024-07-0138101667The ETV6-MECOM fusion protein promotes EMT-related properties by repressing the transactivation activity of E-cadherin promoter in K562 leukemia cellsQian Li0Furong Wang1Xuehong Zhang2Shuqing Liu3Ming-Zhong Sun4Jinsong Yan5Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China; Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, The Second Hospital of Dalian Medical University, Dalian, 116027, ChinaDepartment of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, The Second Hospital of Dalian Medical University, Dalian, 116027, China; Department of Pediatric, Pediatric Oncology and Hematology Center, The Second Hospital of Dalian Medical University, Dalian, 116027, ChinaCenter of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Liaoning, 116044, ChinaDepartment of Biochemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China; Corresponding author. Department of Biochemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China; Liaoning Key Laboratory of Cancer Stem Cell Research, Dalian Medical University, Dalian, 116044, China; Corresponding author. Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, The Second Hospital of Dalian Medical University, Dalian, 116027, China; Department of Pediatric, Pediatric Oncology and Hematology Center, The Second Hospital of Dalian Medical University, Dalian, 116027, China; Corresponding author. Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian, 116027, China.The ETV6-MECOM fusion gene, produced by the rare and recurrent chromosomal translocation t(3; 12) (q26; p13), is associated with high mortality and short survival in myeloid leukemia. However, its function and underlying mechanisms in leukemia progression remain unknown. In this study, leukemia-stable K562 cells expressing the ETV6-MECOM fusion protein were used to investigate the effects of the ETV6-MECOM oncoprotein. K562-ETV6-MECOM cells were undifferentiated and had reduced colony formation, increased cell migration and invasion, and increased sphere number and diameter in a spheroid formation assay, presenting epithelial-to-mesenchymal transition (EMT) traits. The expression of E-cadherin, a hallmark of EMT, was significantly downregulated at the transcriptional and translational level in K562-ETV6-MECOM cells to explore the mechanistic basis of EMT. Stepwise truncation, DNA sequence deletion, mutation analysis for E-cadherin promoter transactivation, and a dual luciferase assay indicated that the regulatory region of ETV6-MECOM is located in the DNA motif −1116 TTAAAA−1111 of E-cadherin promoter. Moreover, a chromatin immunoprecipitation assay showed that this oncoprotein binds to the DNA motif −1116 TTAAAA−1111 with the anti-EVI1 antibody. Although ETV6-MECOM upregulated the expressions of EMT master regulators, including SNAIL, SLUG, ZEB2, and TWIST2, their knockdown had no effect on EMT-related properties. However, overexpression of E-cadherin eliminated EMT traits in the presence of the ETV6-MECOM oncoprotein. These data confirmed that the ETV6-MECOM oncoprotein, not SNAIL, SLUG, ZEB2, or TWIST2, plays a critical role in inducing EMT traits in leukemia K562 cells. ETV6-MECOM induces EMT-related properties by downregulating the transcriptional expression of E-cadherin and repressing its transactivation activity by binding to its core motif −1116TTAAAA−1111 in leukemia K562 cells. These findings could contribute to the development of a therapeutic target for patients with myeloid leukemia characterized by ETV6-MECOM.http://www.sciencedirect.com/science/article/pii/S2405580824000311ETV6-MECOME-cadherin promoterEMTTransactivationLeukemia |
| spellingShingle | Qian Li Furong Wang Xuehong Zhang Shuqing Liu Ming-Zhong Sun Jinsong Yan The ETV6-MECOM fusion protein promotes EMT-related properties by repressing the transactivation activity of E-cadherin promoter in K562 leukemia cells Biochemistry and Biophysics Reports ETV6-MECOM E-cadherin promoter EMT Transactivation Leukemia |
| title | The ETV6-MECOM fusion protein promotes EMT-related properties by repressing the transactivation activity of E-cadherin promoter in K562 leukemia cells |
| title_full | The ETV6-MECOM fusion protein promotes EMT-related properties by repressing the transactivation activity of E-cadherin promoter in K562 leukemia cells |
| title_fullStr | The ETV6-MECOM fusion protein promotes EMT-related properties by repressing the transactivation activity of E-cadherin promoter in K562 leukemia cells |
| title_full_unstemmed | The ETV6-MECOM fusion protein promotes EMT-related properties by repressing the transactivation activity of E-cadherin promoter in K562 leukemia cells |
| title_short | The ETV6-MECOM fusion protein promotes EMT-related properties by repressing the transactivation activity of E-cadherin promoter in K562 leukemia cells |
| title_sort | etv6 mecom fusion protein promotes emt related properties by repressing the transactivation activity of e cadherin promoter in k562 leukemia cells |
| topic | ETV6-MECOM E-cadherin promoter EMT Transactivation Leukemia |
| url | http://www.sciencedirect.com/science/article/pii/S2405580824000311 |
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