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dc.contributor.authorTiffen, JC
dc.contributor.authorGunatilake, D
dc.contributor.authorGallagher, SJ
dc.contributor.authorGowrishankar, K
dc.contributor.authorHeinemann, A
dc.contributor.authorCullinane, C
dc.contributor.authorDutton-Regester, K
dc.contributor.authorPupo, GM
dc.contributor.authorStrbenac, D
dc.contributor.authorYang, JY
dc.contributor.authorMadore, J
dc.contributor.authorMann, GJ
dc.contributor.authorHayward, NK
dc.contributor.authorMcArthur, GA
dc.contributor.authorFilipp, FV
dc.contributor.authorHersey, P
dc.date.accessioned2021-02-04T01:32:29Z
dc.date.available2021-02-04T01:32:29Z
dc.date.issued2015-09-29
dc.identifierpii: 4809
dc.identifier.citationTiffen, 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.
dc.identifier.issn1949-2553
dc.identifier.urihttp://hdl.handle.net/11343/259395
dc.description.abstractThe 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.
dc.languageEnglish
dc.publisherIMPACT JOURNALS LLC
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleTargeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes
dc.typeJournal Article
dc.identifier.doi10.18632/oncotarget.4809
melbourne.affiliation.departmentMelbourne Medical School
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
melbourne.source.titleOncotarget
melbourne.source.volume6
melbourne.source.issue29
melbourne.source.pages27023-27036
dc.rights.licenseCC BY
melbourne.elementsid1071122
melbourne.contributor.authorCullinane, Carleen
melbourne.contributor.authorMcArthur, Grant
dc.identifier.eissn1949-2553
melbourne.accessrightsOpen Access


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