Mutant idh1 depletion downregulates integrins and impairs chondrosarcoma growth

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

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number141
JournalCancers
Volume12
Issue number1
DOIs
StatePublished - Jan 2020

Keywords

  • 2‐hydroxyglutarate
  • CRISPR/Cas9
  • Chondrosarcoma
  • IDH mutation
  • Integrin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Mutant idh1 depletion downregulates integrins and impairs chondrosarcoma growth'. Together they form a unique fingerprint.

  • Cite this

    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. (2020). Mutant idh1 depletion downregulates integrins and impairs chondrosarcoma growth. Cancers, 12(1), [141]. https://doi.org/10.3390/cancers12010141