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| Status |
Public on Nov 15, 2019 |
| Title |
Transcriptional responses of human melanoma cells to EZH2 inhibition |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
The epigenetic modifier EZH2 is part of the polycomb repressive complex that suppresses gene expression via histone methylation. Activating mutations in EZH2 are found in a subset of melanoma that contributes to disease progression by inactivating tumor suppressor genes. In this study we have targeted EZH2 with a specific inhibitor (GSK126) or depleted EZH2 protein by stable shRNA knockdown. We show that inhibition of EZH2 has potent effects on the growth of both wild-type and EZH2 mutant human melanoma in vitro particularly in cell lines harboring the EZH2Y646 activating mutation. This was associated with cell cycle arrest, reduced proliferative capacity in both 2D and 3D culture systems, and induction of apoptosis. The latter was caspase independent and mediated by the release of apoptosis inducing factor (AIFM1) from mitochondria. Gene expression arrays showed that several well characterized tumor suppressor genes were reactivated by EZH2 inhibition. This included activating transcription factor 3 (ATF3) that was validated as an EZH2 target gene by ChIP-qPCR. These results emphasize a critical role for EZH2 in the proliferation and viability of melanoma and highlight the potential for targeted therapy against EZH2 in treatment of patients with melanoma.
Tiffen JC, Gunatilake D, Gallagher SJ, Gowrishankar K, Heinemann A, Cullinane C, et al. Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes. Oncotarget 2015;12:12
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| Overall design |
Total RNA was obtained from cultured human melanoma cell lines treated with either EZH2 inhibitor GSK126 (7.5 micromolar) or DMSO carrier control for either 8 hr or 48 hr and analysed on Illumina HumanHT-12 v4 BeadChip arrays. Four seperate cell lines were treated with all experiments performed in biological duplicates. There are a total of 32 samples.
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| Contributor(s) |
Tiffen JC, Gallagher SJ, Hersey P |
| Citation(s) |
26304929 |
| |
| Submission date |
Nov 14, 2019 |
| Last update date |
Jan 24, 2020 |
| Contact name |
Stuart J Gallagher |
| E-mail(s) |
s.gallagher@centenary.org.au
|
| Phone |
61 2 9565 6100
|
| Organization name |
Centenary Institute
|
| Department |
Melanoma Oncology
|
| Street address |
Building 93, RPA Hospital
|
| City |
Camperdown |
| State/province |
NSW |
| ZIP/Postal code |
2050 |
| Country |
Australia |
| |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (32)
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| Relations |
| BioProject |
PRJNA589591 |
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