Global role of IGF2BP1 in controlling the expression of Wnt/β-catenin-regulated genes in colorectal cancer cells
Introduction: Wnt/β-catenin signaling controls cell division and lineage specification during embryonic development, and is crucial for stem cells maintenance and gut tissue regeneration in adults. Aberrant activation of Wnt/β-catenin signaling is also essential for the pathogenesis of a variety of...
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1236356/full |
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| author | Vikash Singh Vonn Walter Irina Elcheva Yuka Imamura Kawasawa Vladimir S. Spiegelman |
| author_facet | Vikash Singh Vonn Walter Irina Elcheva Yuka Imamura Kawasawa Vladimir S. Spiegelman |
| author_sort | Vikash Singh |
| collection | DOAJ |
| description | Introduction: Wnt/β-catenin signaling controls cell division and lineage specification during embryonic development, and is crucial for stem cells maintenance and gut tissue regeneration in adults. Aberrant activation of Wnt/β-catenin signaling is also essential for the pathogenesis of a variety of malignancies. The RNA-binding protein IGF2BP1 is a transcriptional target of Wnt/β-catenin signaling, normally expressed during development and often reactivated in cancer cells, where it regulates the stability of oncogenic mRNA.Methods: In this study, we employed iCLIP and RNA sequencing techniques to investigate the role of IGF2BP1 in the post-transcriptional regulation of Wnt/β-catenin-induced genes at a global level within colorectal cancer (CRC) cells characterized by constitutively active Wnt/β-catenin signaling.Results and Discussion: In our study, we show that, in contrast to normal cells, CRC cells exhibit a much stronger dependency on IGF2BP1 expression for Wnt/β-catenin-regulated genes. We show that both untransformed and CRC cells have their unique subsets of Wnt/β-catenin-regulated genes that IGF2BP1 directly controls through binding to their mRNA. Our iCLIP analysis revealed a significant change in the IGF2BP1-binding sites throughout the target transcriptomes and a significant change in the enrichment of 6-mer motifs associated with IGF2BP1 binding in response to Wnt/β-catenin signaling. Our study also revealed a signature of IGF2BP1-regulated genes that are significantly associated with colon cancer-free survival in humans, as well as potential targets for CRC treatment. Overall, this study highlights the complex and context-dependent regulation of Wnt/β-catenin signaling target genes by IGF2BP1 in non-transformed and CRC cells and identifies potential targets for colon cancer treatment. |
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| language | English |
| last_indexed | 2024-03-11T21:21:03Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-8f9bbf6a9f1e4a6bbc8f46f549056a6f2023-09-28T05:55:12ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-09-011110.3389/fcell.2023.12363561236356Global role of IGF2BP1 in controlling the expression of Wnt/β-catenin-regulated genes in colorectal cancer cellsVikash Singh0Vonn Walter1Irina Elcheva2Yuka Imamura Kawasawa3Vladimir S. Spiegelman4Division of Pediatric Hematology and Oncology, Department of Pediatrics, College of Medicine, The Pennsylvania State University, Hershey, PA, United StatesDepartment of Public Health Science, College of Medicine, The Pennsylvania State University, Hershey, PA, United StatesDivision of Pediatric Hematology and Oncology, Department of Pediatrics, College of Medicine, The Pennsylvania State University, Hershey, PA, United StatesDepartment of Pharmacology, College of Medicine, The Pennsylvania State University, Hershey, PA, United StatesDivision of Pediatric Hematology and Oncology, Department of Pediatrics, College of Medicine, The Pennsylvania State University, Hershey, PA, United StatesIntroduction: Wnt/β-catenin signaling controls cell division and lineage specification during embryonic development, and is crucial for stem cells maintenance and gut tissue regeneration in adults. Aberrant activation of Wnt/β-catenin signaling is also essential for the pathogenesis of a variety of malignancies. The RNA-binding protein IGF2BP1 is a transcriptional target of Wnt/β-catenin signaling, normally expressed during development and often reactivated in cancer cells, where it regulates the stability of oncogenic mRNA.Methods: In this study, we employed iCLIP and RNA sequencing techniques to investigate the role of IGF2BP1 in the post-transcriptional regulation of Wnt/β-catenin-induced genes at a global level within colorectal cancer (CRC) cells characterized by constitutively active Wnt/β-catenin signaling.Results and Discussion: In our study, we show that, in contrast to normal cells, CRC cells exhibit a much stronger dependency on IGF2BP1 expression for Wnt/β-catenin-regulated genes. We show that both untransformed and CRC cells have their unique subsets of Wnt/β-catenin-regulated genes that IGF2BP1 directly controls through binding to their mRNA. Our iCLIP analysis revealed a significant change in the IGF2BP1-binding sites throughout the target transcriptomes and a significant change in the enrichment of 6-mer motifs associated with IGF2BP1 binding in response to Wnt/β-catenin signaling. Our study also revealed a signature of IGF2BP1-regulated genes that are significantly associated with colon cancer-free survival in humans, as well as potential targets for CRC treatment. Overall, this study highlights the complex and context-dependent regulation of Wnt/β-catenin signaling target genes by IGF2BP1 in non-transformed and CRC cells and identifies potential targets for colon cancer treatment.https://www.frontiersin.org/articles/10.3389/fcell.2023.1236356/fullWnt/β-cateninIGF2BP1dnTCF7L2iCLIPCRC |
| spellingShingle | Vikash Singh Vonn Walter Irina Elcheva Yuka Imamura Kawasawa Vladimir S. Spiegelman Global role of IGF2BP1 in controlling the expression of Wnt/β-catenin-regulated genes in colorectal cancer cells Frontiers in Cell and Developmental Biology Wnt/β-catenin IGF2BP1 dnTCF7L2 iCLIP CRC |
| title | Global role of IGF2BP1 in controlling the expression of Wnt/β-catenin-regulated genes in colorectal cancer cells |
| title_full | Global role of IGF2BP1 in controlling the expression of Wnt/β-catenin-regulated genes in colorectal cancer cells |
| title_fullStr | Global role of IGF2BP1 in controlling the expression of Wnt/β-catenin-regulated genes in colorectal cancer cells |
| title_full_unstemmed | Global role of IGF2BP1 in controlling the expression of Wnt/β-catenin-regulated genes in colorectal cancer cells |
| title_short | Global role of IGF2BP1 in controlling the expression of Wnt/β-catenin-regulated genes in colorectal cancer cells |
| title_sort | global role of igf2bp1 in controlling the expression of wnt β catenin regulated genes in colorectal cancer cells |
| topic | Wnt/β-catenin IGF2BP1 dnTCF7L2 iCLIP CRC |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1236356/full |
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