Three distinct proliferative signals for multiple myeloma (MM) cell lines induce enhancer of zeste homolog 2 (ezh2) transcript expression. EZH2 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 EZH2 expression is deregulated in MM cell lines and determined the consequence of this activity on proliferation and transformation. We found that EZH2 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, EZH2 expression correlates with proliferation and B-cell terminal differentiation. Significantly, EZH2 protein inhibition by short interference RNA treatment results in MM cell growth arrest. Conversely, EZH2 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 EZH2 activity. Finally, this is the first report to demonstrate that EZH2 has oncogenic activity in vivo, and that cell transformation and tumor formation require histone methyltransferase activity.
Bibliographical noteFunding Information:
We thank Dr AP Otte, University of Amsterdam, The Netherlands, for providing antibodies and reagents. We also acknowledge the assistance of Dr Mesher and Dr Shimizu at the University of Minnesota in allowing the use of specific equipment. This study was supported by grants from the National Institute of Health (PO1 CA62242), from the Multiple Myeloma Research Foundation (BVN) and the National Institute of Health Cancer Biology Training Grant CA09138 (PAC).