Epigenetic reprogramming by tumor-derived EZH2 gain-of-function mutations promotes aggressive 3D cell morphologies and enhances melanoma tumor growth
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Anthony M. Barsotti1, Michael Ryskin1, Wenyan Zhong1, Wei-Guo Zhang1, Andreas Giannakou1, Christine Loreth2, Veronica Diesl2, Maximillian Follettie1,2, Jonathon Golas1, Michelle Lee4, Timothy Nichols4, Conglin Fan3, Gang Li3, Stephen Dann3, Valeria R. Fantin3, Kim Arndt1, Dominique Verhelle3, Robert A. Rollins1
1Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA
2Oncology Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02140, USA
3Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA
4Drug Safety Research and Development, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA
Robert A. Rollins, e-mail: [email protected]
Keywords: EZH2, EZH2 mutations, cancer epigenetics, melanoma, 3D culture, motility, Axonal guidance
Received: October 07, 2014 Accepted: November 16, 2014 Published: January 22, 2015
In addition to genetic alterations, cancer cells are characterized by myriad epigenetic changes. EZH2 is a histone methyltransferase that is over-expressed and mutated in cancer. The EZH2 gain-of-function (GOF) mutations first identified in lymphomas have recently been reported in melanoma (~2%) but remain uncharacterized. We expressed multiple EZH2 GOF mutations in the A375 metastatic skin melanoma cell line and observed both increased H3K27me3 and dramatic changes in 3D culture morphology. In these cells, prominent morphological changes were accompanied by a decrease in cell contractility and an increase in collective cell migration. At the molecular level, we observed significant alteration of the axonal guidance pathway, a pathway intricately involved in the regulation of cell shape and motility. Furthermore, the aggressive 3D morphology of EZH2 GOF-expressing melanoma cells (both endogenous and ectopic) was attenuated by EZH2 catalytic inhibition. Finally, A375 cells expressing exogenous EZH2 GOF mutants formed larger tumors than control cells in mouse xenograft studies. This study not only demonstrates the first functional characterization of EZH2 GOF mutants in non-hematopoietic cells, but also provides a rationale for EZH2 catalytic inhibition in melanoma.
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