The m6A modification of LINC01133 suppresses ER+ breast cancer progression by modulating IGF2BP2 protein stability via a ubiquitination-dependent mechanism
BackgroundBreast cancer is characterized as highly heterogenous and is a representative model to understand how molecular features of tumor biology determine therapeutic strategy. LINC01133 exhibits opposing expressing patterns across different breast cancer subtypes, yet its roles and mechanisms in...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2025.1608574/full |
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| author | Mai-dong Li Mai-dong Li Ben-jie Shan Lei Wang Shuang Gao Li Hao Hai-yang Yu Yue-yin Pan Yue-yin Pan |
| author_facet | Mai-dong Li Mai-dong Li Ben-jie Shan Lei Wang Shuang Gao Li Hao Hai-yang Yu Yue-yin Pan Yue-yin Pan |
| author_sort | Mai-dong Li |
| collection | DOAJ |
| description | BackgroundBreast cancer is characterized as highly heterogenous and is a representative model to understand how molecular features of tumor biology determine therapeutic strategy. LINC01133 exhibits opposing expressing patterns across different breast cancer subtypes, yet its roles and mechanisms in ER+ breast cancer remain a loaded question.MethodsThe expression of LINC01133 was initially assessed utilizing a public dataset TCGA and subsequently validated within clinical samples through RT-qPCR and in situ hybridization (ISH). To determine the role of LINC01133, various assays, including colony formation, Transwell, 5-ethynyl-2′-deoxyuridine (EdU) labeling, and mouse xenograft experiments, were performed. Additionally, RNA immunoprecipitation (RIP), RNA pull-down, mass spectrometry (MS), and RNA stability assays were conducted to elucidate its mechanisms.ResultsLINC01133 was dramatically downregulated in ER+ breast cancer, which results in unfavorable prognosis. Functionally, LINC01133 inhibited migration and invasion in vitro and metastasis in vivo of ER+ breast cancer cells. Mechanistically, LINC01133 can directly interact with IGF2BP2 protein promoting its ubiquitination and degradation. The downregulation of LINC01133 was mediated by m6A modification, catalyzed by METTL3 and recognized by YTHDF2, causing half-life reduction and accelerated degradation of LINC01133.ConclusionOur findings revealed the downregulation of LINC01133 in ER+ breast cancer and provided novel insight to the role of METTL3/YTHDF2/LINC01133/IGF2BP2 axis in ER+ breast cancer, which might offer a novel perspective in the design and development of novel anticancer drugs. |
| format | Article |
| id | doaj-art-e02ce045e7da408ca4f99eabbfd7ad9f |
| institution | Kabale University |
| issn | 2234-943X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj-art-e02ce045e7da408ca4f99eabbfd7ad9f2025-08-20T03:27:47ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2025-06-011510.3389/fonc.2025.16085741608574The m6A modification of LINC01133 suppresses ER+ breast cancer progression by modulating IGF2BP2 protein stability via a ubiquitination-dependent mechanismMai-dong Li0Mai-dong Li1Ben-jie Shan2Lei Wang3Shuang Gao4Li Hao5Hai-yang Yu6Yue-yin Pan7Yue-yin Pan8Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Medical Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Medical Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Orthopaedics, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Medical Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Medical Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Medical Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaCheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Medical Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaBackgroundBreast cancer is characterized as highly heterogenous and is a representative model to understand how molecular features of tumor biology determine therapeutic strategy. LINC01133 exhibits opposing expressing patterns across different breast cancer subtypes, yet its roles and mechanisms in ER+ breast cancer remain a loaded question.MethodsThe expression of LINC01133 was initially assessed utilizing a public dataset TCGA and subsequently validated within clinical samples through RT-qPCR and in situ hybridization (ISH). To determine the role of LINC01133, various assays, including colony formation, Transwell, 5-ethynyl-2′-deoxyuridine (EdU) labeling, and mouse xenograft experiments, were performed. Additionally, RNA immunoprecipitation (RIP), RNA pull-down, mass spectrometry (MS), and RNA stability assays were conducted to elucidate its mechanisms.ResultsLINC01133 was dramatically downregulated in ER+ breast cancer, which results in unfavorable prognosis. Functionally, LINC01133 inhibited migration and invasion in vitro and metastasis in vivo of ER+ breast cancer cells. Mechanistically, LINC01133 can directly interact with IGF2BP2 protein promoting its ubiquitination and degradation. The downregulation of LINC01133 was mediated by m6A modification, catalyzed by METTL3 and recognized by YTHDF2, causing half-life reduction and accelerated degradation of LINC01133.ConclusionOur findings revealed the downregulation of LINC01133 in ER+ breast cancer and provided novel insight to the role of METTL3/YTHDF2/LINC01133/IGF2BP2 axis in ER+ breast cancer, which might offer a novel perspective in the design and development of novel anticancer drugs.https://www.frontiersin.org/articles/10.3389/fonc.2025.1608574/fullLINC01133IGF2BP2m6AMETTL3heterogenous |
| spellingShingle | Mai-dong Li Mai-dong Li Ben-jie Shan Lei Wang Shuang Gao Li Hao Hai-yang Yu Yue-yin Pan Yue-yin Pan The m6A modification of LINC01133 suppresses ER+ breast cancer progression by modulating IGF2BP2 protein stability via a ubiquitination-dependent mechanism Frontiers in Oncology LINC01133 IGF2BP2 m6A METTL3 heterogenous |
| title | The m6A modification of LINC01133 suppresses ER+ breast cancer progression by modulating IGF2BP2 protein stability via a ubiquitination-dependent mechanism |
| title_full | The m6A modification of LINC01133 suppresses ER+ breast cancer progression by modulating IGF2BP2 protein stability via a ubiquitination-dependent mechanism |
| title_fullStr | The m6A modification of LINC01133 suppresses ER+ breast cancer progression by modulating IGF2BP2 protein stability via a ubiquitination-dependent mechanism |
| title_full_unstemmed | The m6A modification of LINC01133 suppresses ER+ breast cancer progression by modulating IGF2BP2 protein stability via a ubiquitination-dependent mechanism |
| title_short | The m6A modification of LINC01133 suppresses ER+ breast cancer progression by modulating IGF2BP2 protein stability via a ubiquitination-dependent mechanism |
| title_sort | m6a modification of linc01133 suppresses er breast cancer progression by modulating igf2bp2 protein stability via a ubiquitination dependent mechanism |
| topic | LINC01133 IGF2BP2 m6A METTL3 heterogenous |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2025.1608574/full |
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