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

Autor:	Barsotti AM; Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA., Ryskin M; Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA., Zhong W; Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA., Zhang WG; Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA., Giannakou A; Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA., Loreth C; Oncology Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02140, USA., Diesl V; Oncology Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02140, USA., Follettie M; Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA.; Oncology Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02140, USA., Golas J; Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA., Lee M; Drug Safety Research and Development, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA., Nichols T; Drug Safety Research and Development, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA., Fan C; Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA., Li G; Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA., Dann S; Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA., Fantin VR; Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA., Arndt K; Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA., Verhelle D; Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA., Rollins RA; Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2015 Feb 20; Vol. 6 (5), pp. 2928-38.
DOI:	10.18632/oncotarget.2758
Abstrakt:	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.
Databáze:	MEDLINE
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