Abstract
Simple SummaryCartilage tumors frequently harbor mutations in the isocitrate dehydrogenase (IDH1 or IDH2) genes. These mutations cause an increase in the levels of the oncometabolite D-2-hydroxyglutarate (D-2-HG), which leads to widespread changes in several cellular processes, including the epigenetic landscape. The aim of our study was to explore whether the methylome of IDH mutant cartilage tumors is altered upon tumor progression and whether these underlying epigenetic vulnerabilities could be used as a target for therapy in both IDH wildtype and IDH mutant high-grade chondrosarcomas. As surgery is nowadays the only treatment option for chondrosarcoma patients, the identification of novel therapeutic strategies remains an important endeavor. The findings in this study show that histone deacetylase (HDAC) inhibition may represent a promising therapeutic strategy for all chondrosarcoma patients, since sensitivity towards this therapeutic option seems independent of the IDH mutation status and the chondrosarcoma subtype.Mutations in the isocitrate dehydrogenase (IDH1 or IDH2) 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 IDH 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 IDH 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.
Highlights
Chondrosarcomas are bone malignancies characterized by the production of cartilage and account for 20% of all malignant bone tumors [1,2]
Hierarchical clustering of the methylome of these 20 IDH mutant primary cartilage tumors resulted in two clusters: a group dominated by benign/low-grade cartilage tumors and a group consisting of solely high-grade chondrosarcomas (Figure 1A)
Alterations in the methylome of IDH mutant cartilage tumors are associated with tumor progression and this study shows that targeting of epigenetic regulators could be a potential therapeutic strategy for both IDH wildtype and IDH mutant chondrosarcoma patients
Summary
Chondrosarcomas are bone malignancies characterized by the production of cartilage and account for 20% of all malignant bone tumors [1,2]. Based on the anatomical location and pathological characteristics of the tumors, chondrosarcomas are divided into several subtypes: conventional chondrosarcoma (85%), dedifferentiated chondrosarcoma (10%), and rare subtypes (5%), which include mesenchymal-, clear cell-, and periosteal chondrosarcomas. Conventional chondrosarcomas are classified into central (85%) and peripheral (15%) tumors, based on their anatomical location (medulla or surface of the bone, respectively) [1,2]. The most important factor to predict metastatic potential and overall survival of patients with conventional chondrosarcoma is histological grading, which is defined by the cellularity and matrix formation of the tumor. Patients with atypical cartilaginous tumor (ACT)/chondrosarcoma grade I have a low metastatic rate and an overall 10-year survival rate of. Patients with high-grade tumors (i.e., grade II and grade III) have an increased metastasis rate (10% and 71%, respectively) and a decreased overall 10-year survival rate
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