title: Epigenetic reprogramming by tumor-derived EZH2 gain-of-function mutations promotes aggressive 3D cell morphologies and enhances melanoma tumor growth.
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.
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA.
authors: Anthony M
authors: AM
authors: Barsotti
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA.
authors: Michael
authors: M
authors: Ryskin
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA.
authors: Wenyan
authors: W
authors: Zhong
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA.
authors: Wei-Guo
authors: WG
authors: Zhang
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA.
authors: Andreas
authors: A
authors: Giannakou
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02140, USA.
authors: Christine
authors: C
authors: Loreth
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02140, USA.
authors: Veronica
authors: V
authors: Diesl
authors: 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.
authors: Maximillian
authors: M
authors: Follettie
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA.
authors: Jonathon
authors: J
authors: Golas
authors: Drug Safety Research and Development, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors: Michelle
authors: M
authors: Lee
authors: Drug Safety Research and Development, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors: Timothy
authors: T
authors: Nichols
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors: Conglin
authors: C
authors: Fan
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors: Gang
authors: G
authors: Li
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors: Stephen
authors: S
authors: Dann
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors: Valeria R
authors: VR
authors: Fantin
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA.
authors: Kim
authors: K
authors: Arndt
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors: Dominique
authors: D
authors: Verhelle
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA.
authors: Robert A
authors: RA
authors: Rollins
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D048430:Cell Shape / Q000187:drug effects; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D009361:Neoplasm Invasiveness; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2