Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth
| Autor: | Andrew E. Rosenberg, Jonathan C. Trent, Joanna DeSalvo, Marzenna Blonska, Xiaodian Sun, Josiane E. Eid, Yuguang Ban, Xi Steven Chen, Luyuan Li, Karina Galoian, Breelyn A. Wilky, Jinbo Yue, Xiaoyu Hu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine Cancer Research IDH1 integrin Integrin 2-hydroxyglutarate medicine.disease_cause lcsh:RC254-282 Article 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation medicine CRISPR/Cas9 chondrosarcoma Mutation biology Chemistry Cell migration musculoskeletal system lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease IDH mutation 030104 developmental biology Isocitrate dehydrogenase Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Chondrosarcoma Carcinogenesis |
| Zdroj: | Cancers Cancers, Vol 12, Iss 1, p 141 (2020) Volume 12 Issue 1 |
| ISSN: | 2072-6694 |
| Popis: | 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 &alpha ketoglutarate (&alpha KG). Instead, &alpha 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 &alpha 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. |
| Databáze: | OpenAIRE |
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