The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression
The overactivation of Wnt/β-catenin signaling is a hallmark of colorectal cancer (CRC) development. We identified the cell adhesion molecule L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. The overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigen...
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MDPI AG
2021-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/7/3552 |
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| author | Sanith Cheriyamundath Anmol Kumar Nancy Gavert Thomas Brabletz Avri Ben-Ze’ev |
| author_facet | Sanith Cheriyamundath Anmol Kumar Nancy Gavert Thomas Brabletz Avri Ben-Ze’ev |
| author_sort | Sanith Cheriyamundath |
| collection | DOAJ |
| description | The overactivation of Wnt/β-catenin signaling is a hallmark of colorectal cancer (CRC) development. We identified the cell adhesion molecule L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. The overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis and liver metastasis, and L1 is exclusively localized in the invasive areas of human CRC tissue. A number of genes are induced after L1 transfection into CRC cells by a mechanism involving the cytoskeletal protein ezrin and the NF-κB pathway. When studying the changes in gene expression in CRC cells overexpressing L1 in which ezrin levels were suppressed by shRNA to ezrin, we discovered the collagen-modifying enzyme lysyl hydroxylase 2 (PLOD2) among these genes. We found that increased PLOD2 expression was required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis and liver metastasis, since the suppression of endogenous PLOD2 expression, or its enzymatic activity, blocked the enhanced tumorigenic properties conferred by L1. The mechanism involved in increased PLOD2 expression by L1 involves ezrin signaling and PLOD2 that affect the SMAD2/3 pathway. We found that PLOD2 is localized in the colonic crypts in the stem cell compartment of the normal mucosa and is found at increased levels in invasive areas of the tumor and, in some cases, throughout the tumor tissue. The therapeutic strategies to target PLOD2 expression might provide a useful approach for CRC treatment. |
| first_indexed | 2024-03-10T12:47:09Z |
| format | Article |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:47:09Z |
| publishDate | 2021-03-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-29780ced58c44e59abb8bea49f37d85b2023-11-21T13:19:37ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01227355210.3390/ijms22073552The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer ProgressionSanith Cheriyamundath0Anmol Kumar1Nancy Gavert2Thomas Brabletz3Avri Ben-Ze’ev4Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, IsraelDepartment of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, IsraelDepartment of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, IsraelExperimental Medicine I, Nikolaus-Feibiger-Center for Molecular Medicine, University of Erlangen-Nuernberg, 91054 Erlangen, GermanyDepartment of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, IsraelThe overactivation of Wnt/β-catenin signaling is a hallmark of colorectal cancer (CRC) development. We identified the cell adhesion molecule L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. The overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis and liver metastasis, and L1 is exclusively localized in the invasive areas of human CRC tissue. A number of genes are induced after L1 transfection into CRC cells by a mechanism involving the cytoskeletal protein ezrin and the NF-κB pathway. When studying the changes in gene expression in CRC cells overexpressing L1 in which ezrin levels were suppressed by shRNA to ezrin, we discovered the collagen-modifying enzyme lysyl hydroxylase 2 (PLOD2) among these genes. We found that increased PLOD2 expression was required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis and liver metastasis, since the suppression of endogenous PLOD2 expression, or its enzymatic activity, blocked the enhanced tumorigenic properties conferred by L1. The mechanism involved in increased PLOD2 expression by L1 involves ezrin signaling and PLOD2 that affect the SMAD2/3 pathway. We found that PLOD2 is localized in the colonic crypts in the stem cell compartment of the normal mucosa and is found at increased levels in invasive areas of the tumor and, in some cases, throughout the tumor tissue. The therapeutic strategies to target PLOD2 expression might provide a useful approach for CRC treatment.https://www.mdpi.com/1422-0067/22/7/3552PLOD2L1colorectal cancerezrininvasion and metastasislysyl hydroxylase 2 |
| spellingShingle | Sanith Cheriyamundath Anmol Kumar Nancy Gavert Thomas Brabletz Avri Ben-Ze’ev The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression International Journal of Molecular Sciences PLOD2 L1 colorectal cancer ezrin invasion and metastasis lysyl hydroxylase 2 |
| title | The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression |
| title_full | The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression |
| title_fullStr | The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression |
| title_full_unstemmed | The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression |
| title_short | The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression |
| title_sort | collagen modifying enzyme plod2 is induced and required during l1 mediated colon cancer progression |
| topic | PLOD2 L1 colorectal cancer ezrin invasion and metastasis lysyl hydroxylase 2 |
| url | https://www.mdpi.com/1422-0067/22/7/3552 |
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