The polycomb group protein enhancer of zeste homolog 2 (EZH 2) is an oncogene that influences myeloma cell growth and the mutant ras phenotype.
Three distinct proliferative signals for multiple myeloma (MM) cell lines induce enhancer of zeste homolog 2 (ezh 2) transcript expression. EZH 2 is a polycomb group protein that mediates repression of gene transcription at the chromatin level through its methyltransferase activity. Normal bone marrow plasma cells do not express ezh2; however, gene expression is induced and correlates with tumor burden during progression of this disease. We therefore investigated how EZH 2 expression is deregulated in MM cell lines and determined the consequence of this activity on proliferation and transformation. We found that EZH 2 protein expression is induced by interleukin 6 (IL-6) in growth factor-dependent cell lines and is constitutive in IL-6-independent cell lines. Furthermore, EZH 2 expression correlates with proliferation and B-cell terminal differentiation. Significantly, EZH 2 protein inhibition by short interference RNA treatment results in MM cell growth arrest. Conversely, EZH 2 ectopic overexpression induces growth factor independence. We found that the growth factor-independent proliferative phenotype in MM cell lines harboring a mutant N- or K-ras gene requires EZH 2 activity. Finally, this is the first report to demonstrate that EZH 2 has oncogenic activity in vivo, and that cell transformation and tumor formation require histone methyltransferase activity.
Croonquist
Paula A
PA
The Graduate Program in Molecular, Cellular, Developmental Biology, and Genetics, University of Minnesota, Minneapolis, MN 55455, USA.
Van Ness
Brian
B
D000818:Animals; D002384:Catalysis; D002454:Cell Differentiation; D002455:Cell Division / Q000235:genetics*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D011905:Genes, ras; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D041681:NIH 3T3 Cells; D010641:Phenotype; D063151:Polycomb Repressive Complex 2; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2