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| Status |
Public on Feb 23, 2022 |
| Title |
Dysregulated lipid metabolism blunts the sensitivity of B16F10 melanoma cells to EZH2 inhibitor |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The sensitivity has been the key issue for EZH2 inhibitor in cancer therapy. Although it has been approved by Food and Drug Administration (FDA) in 2020, the relative narrow scope still limits its clinical application. In this study, we utilized B16F10 melanoma cell line which is resistant to EZH2 inhibitor GSK126 to an extent to investigate the underlying mechanism. We found that although the proliferative phenotype didn't show any difference upon treatment with GSK126 at 10 μM, the transcriptome and metabolome changed profoundly. Gene set enrichment analysis and metabolites pathway enrichment analysis revealed that GSK126 induced broad shifts in glucose, amino acids and lipid metabolism. Lipid synthesis were strengthened with elevated abundance of unsaturated fatty acids. We also found attenuated tricarboxylic acid cycle metabolism, and decreased amino acids levels. The liver lipid accumulation and the increased blood triglycerides level after GSK126 treatment were further confirmed in a mouse model. Indeed, the combination of GSK126 and lipolysis agent fenofibrate significantly attenuated the proliferation of B16F10 and increased the sensitivity to GSK126. Therefore, the dysregulated lipid metabolism blunts the sensitivity of B16F10 to GSK126. This study uncovered the iceberg under the sea and identified the Achilles heel of EZH2 inhibitor, so that it provides the novel strategy for further combination therapy.
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| Overall design |
mRNA profiles of GSK126-treated and DMSO-treated B16F10 melanoma cells
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| Contributor(s) |
Zhang T, Guo Z, Gong Y, Wang Y, Yin Q, Xue L |
| Citation(s) |
35158113 |
| |
| Submission date |
Dec 11, 2020 |
| Last update date |
Feb 24, 2022 |
| Contact name |
Qianqian Yin |
| Organization name |
Peking University Third Hospital
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| Department |
Center of Basic Medical Research
|
| Street address |
49 North Garden Road, Haidian District
|
| City |
BEIJING |
| ZIP/Postal code |
100191 |
| Country |
China |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA684616 |
| SRA |
SRP297710 |
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