Beyond the Influence of IDH Mutations: Exploring Epigenetic Vulnerabilities in Chondrosarcoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. IDH Mutant Chondrosarcomas Have Increased Hypermethylation with Increasing Histological Grade
2.2. Epigenetic Compound Screening Identifies HDAC Enzymes as Important Epigenetic Regulators in Chondrosarcoma, Independent of the IDH Mutation Status
2.3. Chondrosarcoma Cell Lines Mainly Rely on the Expression of HDAC Class I Subtypes
2.4. Chondrosarcoma Cell Lines Are Sensitive to Romidepsin, Irrespective of the Chondrosarcoma Subtype or IDH Mutation Status
2.5. HDAC Inhibitor Combination Drug Screen Identifies Bcl-2 Family Member Inhibitors and Metabolic Compounds as Potential Combination Treatment Strategies
2.6. Romidepsin Sensitizes Chondrosarcoma Cells to Bcl-2 Family Member Inhibitors and Affects the Expression of Both Anti- and Pro-Apoptotic Proteins
3. Discussion
4. Materials and Methods
4.1. DNA Methylation Array
4.2. Compounds
4.3. Cell Culture
4.4. Primary Epigenetics Compound Screen
4.5. Secondary Epigenetics Compound Screen
4.6. HDAC Inhibitor Combination Drug Screen
4.7. Cell Viability and Nuclei Count Assays
4.8. siRNA Transfection
4.9. Next Generation RNA Sequencing Analysis
4.10. Apoptosis and Cell Cycle Assays
4.11. Western Blotting
4.12. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cell Line | Subtype | IDH Status | 2D Cell Culture | 3D Cell Culture | |
---|---|---|---|---|---|
GR50 (nM) | IC50 (nM) | IC50 (nM) | |||
MCS170 | Mesenchymal | Wildtype | 0.89 | 2.69 | - |
L835 | Central conventional | IDH1 R132C | 0.97 | 29.2 | - |
JJ012 + AGI-5198 | Central conventional | IDH1 R132G (inhibited) | 1.06 | 0.96 | - |
SW1353 | Central conventional | IDH2 R172S | 1.10 | 1.01 | 2.00 |
HT1080 | Dedifferentiated | IDH1 R132C | 1.10 | 0.99 | - |
CH3573 | Central conventional | Wildtype | 1.26 | 1.37 | - |
L2975 | Dedifferentiated | IDH2 R172W | 1.27 | 1.29 | - |
L3252B | Dedifferentiated | Wildtype | 1.30 | 1.51 | - |
CH2879 | Central conventional | Wildtype | 1.79 | 1.61 | 2.96 |
NDCS1 | Dedifferentiated | Wildtype | 1.92 | 1.57 | - |
JJ012 | Central conventional | IDH1 R132G | 1.96 | 1.71 | 5.08 |
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Venneker, S.; Kruisselbrink, A.B.; Baranski, Z.; Palubeckaite, I.; Briaire-de Bruijn, I.H.; Oosting, J.; French, P.J.; Danen, E.H.J.; Bovée, J.V.M.G. Beyond the Influence of IDH Mutations: Exploring Epigenetic Vulnerabilities in Chondrosarcoma. Cancers 2020, 12, 3589. https://doi.org/10.3390/cancers12123589
Venneker S, Kruisselbrink AB, Baranski Z, Palubeckaite I, Briaire-de Bruijn IH, Oosting J, French PJ, Danen EHJ, Bovée JVMG. Beyond the Influence of IDH Mutations: Exploring Epigenetic Vulnerabilities in Chondrosarcoma. Cancers. 2020; 12(12):3589. https://doi.org/10.3390/cancers12123589
Chicago/Turabian StyleVenneker, Sanne, Alwine B. Kruisselbrink, Zuzanna Baranski, Ieva Palubeckaite, Inge H. Briaire-de Bruijn, Jan Oosting, Pim J. French, Erik H. J. Danen, and Judith V. M. G. Bovée. 2020. "Beyond the Influence of IDH Mutations: Exploring Epigenetic Vulnerabilities in Chondrosarcoma" Cancers 12, no. 12: 3589. https://doi.org/10.3390/cancers12123589