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

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    43
    Author
    Tiffen, JC; Gunatilake, D; Gallagher, SJ; Gowrishankar, K; Heinemann, A; Cullinane, C; Dutton-Regester, K; Pupo, GM; Strbenac, D; Yang, JY; ...
    Date
    2015-09-29
    Source Title
    Oncotarget
    Publisher
    IMPACT JOURNALS LLC
    University of Melbourne Author/s
    Cullinane, Carleen; McArthur, Grant
    Affiliation
    Melbourne Medical School
    Sir Peter MacCallum Department of Oncology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Tiffen, J. C., Gunatilake, D., Gallagher, S. J., Gowrishankar, K., Heinemann, A., Cullinane, C., Dutton-Regester, K., Pupo, G. M., Strbenac, D., Yang, J. Y., Madore, J., Mann, G. J., Hayward, N. K., McArthur, G. A., Filipp, F. V. & Hersey, P. (2015). Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes. ONCOTARGET, 6 (29), pp.27023-27036. https://doi.org/10.18632/oncotarget.4809.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/259395
    DOI
    10.18632/oncotarget.4809
    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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