Portal de Periódicos da CAPES

Epigenetic reprogramming by tumor-derived EZH2 gain-of-function mutations promotes aggressive 3D cell morphologies and enhances melanoma tumor growth

2015; Impact Journals LLC; Volume: 6; Issue: 5 Linguagem: Inglês

10.18632/oncotarget.2758

1949-2553

Anthony M. Barsotti, Michael Ryskin, Wenyan Zhong, Weiguo Zhang, Andreas Giannakou, Christine Loreth, Veronica Diesl, Maximillian T. Follettie, Jonathon Golas, Michelle Lee, Timothy C. Nichols, Conglin Fan, Gang Li, Stephen G. Dann, Valeria R. Fantin, Kim Arndt, Dominique Verhelle, Robert A. Rollins,

Histone Deacetylase Inhibitors Research

// Anthony M. Barsotti 1 , Michael Ryskin 1 , Wenyan Zhong 1 , Wei-Guo Zhang 1 , Andreas Giannakou 1 , Christine Loreth 2 , Veronica Diesl 2 , Maximillian Follettie 1, 2 , Jonathon Golas 1 , Michelle Lee 4 , Timothy Nichols 4 , Conglin Fan 3 , Gang Li 3 , Stephen Dann 3 , Valeria R. Fantin 3 , Kim Arndt 1 , Dominique Verhelle 3 , Robert A. Rollins 1 1 Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA 2 Oncology Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02140, USA 3 Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA 4 Drug Safety Research and Development, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA Correspondence to: Robert A. Rollins, e-mail: Robert.Rollins@pfizer.com Keywords: EZH2, EZH2 mutations, cancer epigenetics, melanoma, 3D culture, motility, Axonal guidance Received: October 07, 2014 Accepted: November 16, 2014 Published: January 22, 2015 ABSTRACT 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.