Beyond the Influence of IDH Mutations: Exploring Epigenetic Vulnerabilities in Chondrosarcoma

Mutations in the isocitrate dehydrogenase ( or ) genes are common in enchondromas and chondrosarcomas, and lead to elevated levels of the oncometabolite D-2-hydroxyglutarate causing widespread changes in the epigenetic landscape of these tumors. With the use of a DNA methylation array, we explored w...

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Bibliographic Details
Published in:Cancers 2020-11, Vol.12 (12), p.3589
Main Authors: Venneker, Sanne, Kruisselbrink, Alwine B, Baranski, Zuzanna, Palubeckaite, Ieva, Briaire-de Bruijn, Inge H, Oosting, Jan, French, Pim J, Danen, Erik H J, Bovée, Judith V M G
Format: Article
Language:English
Subjects:
Apoptosis
Bcl-2 protein
Cartilage
Cell growth
Chemotherapy
Chondrosarcoma
Deoxyribonucleic acid
DNA
DNA methylation
Enzymes
Epigenetics
Gene expression
Genotype & phenotype
Histone deacetylase
Isocitrate dehydrogenase
Kinases
Medical prognosis
Metastasis
Mutation
Signal transduction
siRNA
Tumors
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Summary:Mutations in the isocitrate dehydrogenase ( or ) genes are common in enchondromas and chondrosarcomas, and lead to elevated levels of the oncometabolite D-2-hydroxyglutarate causing widespread changes in the epigenetic landscape of these tumors. With the use of a DNA methylation array, we explored whether the methylome is altered upon progression from mutant enchondroma towards high-grade chondrosarcoma. High-grade tumors show an overall increase in the number of highly methylated genes, indicating that remodeling of the methylome is associated with tumor progression. Therefore, an epigenetics compound screen was performed in five chondrosarcoma cell lines to therapeutically explore these underlying epigenetic vulnerabilities. Chondrosarcomas demonstrated high sensitivity to histone deacetylase (HDAC) inhibition in both 2D and 3D in vitro models, independent of the mutation status or the chondrosarcoma subtype. siRNA knockdown and RNA expression data showed that chondrosarcomas rely on the expression of multiple HDACs, especially class I subtypes. Furthermore, class I HDAC inhibition sensitized chondrosarcoma to glutaminolysis and Bcl-2 family member inhibitors, suggesting that HDACs define the metabolic state and apoptotic threshold in chondrosarcoma. Taken together, HDAC inhibition may represent a promising targeted therapeutic strategy for chondrosarcoma patients, either as monotherapy or as part of combination treatment regimens.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers12123589