ROLE OF EZH2 IN NASAL TYPE NATURAL KILLER T CELL LYMPHOMA (NKTL)

Abstract

EZH2, the enzymatic subunit of the PRC2 complex, usually acts as a transcriptional repressor by methylating Histone H3 at lysine 27. In natural killer/ T-cell lymphoma (NKTL), our previous study showed that the overexpressed and oncogenic EZH2 was independent of its methyltransferase activity. In this study, we further exploited possible roles of EZH2 in NKTL, by investigating how the oncogenic role of EZH2 was regulated, how EZH2 regulated downstream targets, what kind of cellular functions EZH2 performed, and how to target oncogenic EZH2 in NKTL for therapeutic purposes. We characterized two upstream regulators of EZH2: JAK3, which could switch EZH2 to its non-canonical and oncogenic role in NKTL through site-specific phosphorylation; and MELK, which could inhibit proteasome-mediated degradation of EZH2. Targeting JAK3, MELK or both were very effective to harness the oncogenic EZH2 in NKTL. Roles of EZH2 in mediating other cellular processes in NKTL were also suggested.