Oncotarget

Research Papers:

Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes

Jessamy C. Tiffen, Dilini Gunatilake, Stuart J. Gallagher, Kavitha Gowrishankar, Anja Heinemann, Carleen Cullinane, Ken Dutton-Regester, Gulietta M. Pupo, Dario Strbenac, Jean Y. Yang, Jason Madore, Graham J. Mann, Nicholas K. Hayward, Grant A. McArthur, Fabian V. Filipp and Peter Hersey _

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Oncotarget. 2015; 6:27023-27036. https://doi.org/10.18632/oncotarget.4809

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Abstract

Jessamy C. Tiffen1,2,8, Dilini Gunatilake1,2,8, Stuart J. Gallagher1,2,8, Kavitha Gowrishankar1,2,8, Anja Heinemann1,2,8, Carleen Cullinane3, Ken Dutton-Regester4, Gulietta M. Pupo5, Dario Strbenac6, Jean Y. Yang6, Jason Madore7,8, Graham J. Mann5,6,8, Nicholas K. Hayward4, Grant A. McArthur3,9, Fabian V. Filipp10, Peter Hersey1,2,8

1Melanoma Immunology and Oncology Group, Centenary Institute, University of Sydney, NSW, Australia

2Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, NSW, Australia

3Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

4Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

5Center for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, NSW, Australia

6School of Mathematics and Statistics, University of Sydney, NSW, Australia

7Sydney Medical School, University of Sydney, NSW, Australia

8Melanoma Institute Australia, Crows Nest, Sydney, NSW, Australia

9Oncogenic Signalling and Growth Control Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

10Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, Merced, CA, USA

Correspondence to:

Peter Hersey, e-mail: p.hersey@centenary.org.au

Keywords: melanoma, EZH2, H3K27me3, epigenetics, targeted therapy

Received: April 20, 2015     Accepted: August 03, 2015     Published: August 12, 2015

ABSTRACT

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.


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