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Open AccessArticle

Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth

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Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Department of Medicine, Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136, USA
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School of Medicine and Life Sciences, University of Jinan Shandong Academy of Medical Sciences, Jinan 250000, Shandong, China
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Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250000, Shandong, China
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Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA
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Department of Orthopaedic Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(1), 141; https://doi.org/10.3390/cancers12010141
Received: 25 October 2019 / Revised: 23 December 2019 / Accepted: 31 December 2019 / Published: 6 January 2020
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 (IDH1mut) 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 IDH1mut knockout cells. Loss of IDH1mut also led to a marked attenuation of chondrosarcoma formation and D-2HG production in a xenograft model. In addition, RNA-Seq analysis of IDH1mut 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 IDH1mut knockout abrogates chondrosarcoma genesis through modulation of integrins. This suggests that integrin molecules are appealing candidates for combinatorial regimens with IDH1mut inhibitors for chondrosarcomas that harbor this mutation. View Full-Text
Keywords: chondrosarcoma; IDH mutation; integrin; 2-hydroxyglutarate; CRISPR/Cas9 chondrosarcoma; IDH mutation; integrin; 2-hydroxyglutarate; CRISPR/Cas9
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Li, L.; Hu, X.; Eid, J.E.; Rosenberg, A.E.; Wilky, B.A.; Ban, Y.; Sun, X.; Galoian, K.; DeSalvo, J.; Yue, J.; Chen, X.S.; Blonska, M.; Trent, J.C. Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth. Cancers 2020, 12, 141.

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