Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth
Chondrosarcomas are a heterogeneous group of malignant bone tumors that produce hyaline cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers, including conventional and dedifferentiated chondrosarcomas. These mutations lead to the in...
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doaj-30d80582cf28496c92c9b5866aba96a82020-11-25T01:42:27ZengMDPI AGCancers2072-66942020-01-0112114110.3390/cancers12010141cancers12010141Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma GrowthLuyuan Li0Xiaoyu Hu1Josiane E. Eid2Andrew E. Rosenberg3Breelyn A. Wilky4Yuguang Ban5Xiaodian Sun6Karina Galoian7Joanna DeSalvo8Jinbo Yue9Xi Steven Chen10Marzenna Blonska11Jonathan C. Trent12Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USADepartment of Medicine, Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USADepartment of Medicine, Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USASylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136, USADepartment of Medicine, Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USASylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136, USASylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136, USADepartment of Orthopaedic Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USADepartment of Medicine, Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USASchool of Medicine and Life Sciences, University of Jinan Shandong Academy of Medical Sciences, Jinan 250000, Shandong, ChinaSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136, USADepartment of Medicine, Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USADepartment of Medicine, Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USAChondrosarcomas are a heterogeneous group of malignant bone tumors that produce hyaline cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers, including conventional and dedifferentiated chondrosarcomas. These mutations lead to the inability of IDH to convert isocitrate into α-ketoglutarate (α-KG). Instead, α-KG is reduced into D-2-hydroxyglutarate (D-2HG), an oncometabolite. IDH mutations and D-2HG are thought to contribute to tumorigenesis due to the role of D-2HG as a competitive inhibitor of α-KG-dependent dioxygenases. However, the function of IDH mutations in chondrosarcomas has not been clearly defined. In this study, we knocked out mutant IDH1 (IDH1<sup>mut</sup>) in two chondrosarcoma cell lines using the CRISPR/Cas9 system. We observed that D-2HG production, anchorage-independent growth, and cell migration were significantly suppressed in the IDH1<sup>mut</sup> knockout cells. Loss of IDH1<sup>mut</sup> also led to a marked attenuation of chondrosarcoma formation and D-2HG production in a xenograft model. In addition, RNA-Seq analysis of IDH1<sup>mut</sup> knockout cells revealed downregulation of several integrin genes, including those of integrin alpha 5 (ITGA5) and integrin beta 5 (ITGB5). We further demonstrated that deregulation of integrin-mediated processes contributed to the tumorigenicity of IDH1-mutant chondrosarcoma cells. Our findings showed that IDH1<sup>mut</sup> knockout abrogates chondrosarcoma genesis through modulation of integrins. This suggests that integrin molecules are appealing candidates for combinatorial regimens with IDH1<sup>mut</sup> inhibitors for chondrosarcomas that harbor this mutation.https://www.mdpi.com/2072-6694/12/1/141chondrosarcomaidh mutationintegrin2-hydroxyglutaratecrispr/cas9 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Luyuan Li Xiaoyu Hu Josiane E. Eid Andrew E. Rosenberg Breelyn A. Wilky Yuguang Ban Xiaodian Sun Karina Galoian Joanna DeSalvo Jinbo Yue Xi Steven Chen Marzenna Blonska Jonathan C. Trent |
spellingShingle |
Luyuan Li Xiaoyu Hu Josiane E. Eid Andrew E. Rosenberg Breelyn A. Wilky Yuguang Ban Xiaodian Sun Karina Galoian Joanna DeSalvo Jinbo Yue Xi Steven Chen Marzenna Blonska Jonathan C. Trent Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth Cancers chondrosarcoma idh mutation integrin 2-hydroxyglutarate crispr/cas9 |
author_facet |
Luyuan Li Xiaoyu Hu Josiane E. Eid Andrew E. Rosenberg Breelyn A. Wilky Yuguang Ban Xiaodian Sun Karina Galoian Joanna DeSalvo Jinbo Yue Xi Steven Chen Marzenna Blonska Jonathan C. Trent |
author_sort |
Luyuan Li |
title |
Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth |
title_short |
Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth |
title_full |
Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth |
title_fullStr |
Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth |
title_full_unstemmed |
Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth |
title_sort |
mutant idh1 depletion downregulates integrins and impairs chondrosarcoma growth |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-01-01 |
description |
Chondrosarcomas are a heterogeneous group of malignant bone tumors that produce hyaline cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers, including conventional and dedifferentiated chondrosarcomas. These mutations lead to the inability of IDH to convert isocitrate into α-ketoglutarate (α-KG). Instead, α-KG is reduced into D-2-hydroxyglutarate (D-2HG), an oncometabolite. IDH mutations and D-2HG are thought to contribute to tumorigenesis due to the role of D-2HG as a competitive inhibitor of α-KG-dependent dioxygenases. However, the function of IDH mutations in chondrosarcomas has not been clearly defined. In this study, we knocked out mutant IDH1 (IDH1<sup>mut</sup>) in two chondrosarcoma cell lines using the CRISPR/Cas9 system. We observed that D-2HG production, anchorage-independent growth, and cell migration were significantly suppressed in the IDH1<sup>mut</sup> knockout cells. Loss of IDH1<sup>mut</sup> also led to a marked attenuation of chondrosarcoma formation and D-2HG production in a xenograft model. In addition, RNA-Seq analysis of IDH1<sup>mut</sup> knockout cells revealed downregulation of several integrin genes, including those of integrin alpha 5 (ITGA5) and integrin beta 5 (ITGB5). We further demonstrated that deregulation of integrin-mediated processes contributed to the tumorigenicity of IDH1-mutant chondrosarcoma cells. Our findings showed that IDH1<sup>mut</sup> knockout abrogates chondrosarcoma genesis through modulation of integrins. This suggests that integrin molecules are appealing candidates for combinatorial regimens with IDH1<sup>mut</sup> inhibitors for chondrosarcomas that harbor this mutation. |
topic |
chondrosarcoma idh mutation integrin 2-hydroxyglutarate crispr/cas9 |
url |
https://www.mdpi.com/2072-6694/12/1/141 |
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