EZH2 overexpression in natural killer /T-cell lymphoma confers growth advantage independently of histone methyltransferase activity Running Title: EZH2 in natural killer / T-cell lymphoma

The role of EZH2 in cancer is complex and may vary depending on the cellular context. We found that EZH2 is aberrantly overexpressed in the majority of natural killer / T-cell lymphoma (NKTL), an aggressive lymphoid malignancy with very poor prognosis. We show that EZH2 upregulation is mediated by MYC-induced repression of its regulatory miRNAs and EZH2 exerts oncogenic properties in NKTL. Ectopic expression of EZH2 in both primary NK cells and NKTL cell lines lead to a significant growth advantage. Conversely, knock-down of EZH2 in NKTL cell lines results in cell growth inhibition. Intriguingly, ectopic EZH2 mutant deficient for histone methyltransferase activity is also able to confer growth advantage and rescue the growth inhibition upon endogenous EZH2 depletion in NKTL cells, indicating an oncogenic role of EZH2 independent of its gene silencing activity. Mechanistically, we show that EZH2 directly promotes the transcription of Cyclin D1 and this effect is independent of its enzymatic activity. Furthermore, depletion of EZH2 using a PRC2 inhibitor DZNep significantly inhibits growth of NK tumor cells. Therefore, our study has uncovered an oncogenic role of EZH2 independent of its methyltransferase activity in NKTL, and suggests that targeting EZH2 may have therapeutic utility in this lymphoma. For personal use only. on January 11, 2018. by guest www.bloodjournal.org From