FUNCTIONAL RELEVANCE AND DOWNSTREAM PATHWAYS OF EZH2 IN NASAL TYPE NATURAL KILLER T-CELL LYMPHOMA (NKTL)

Abstract

Extranodal nasal-type natural killer/T-cell lymphoma (NKTL) is a rare and aggressive form of lymphoma with a poor survival rate. A better understanding of the molecular mechanisms will aid our understanding and help the development of targeted drugs or drug combination that will improve patient survival rate. Our group previously showed that EZH2, a histone methyltransferase, is abnormally over-expressed and confers growth advantage to NK cells. To examine the functional importance of targeting Ezh2 in NKTL, we treated NKTL cells with DZNep, an inhibitor of Ezh2. We found that DZNep effectively induces apoptosis in NKTL cells, and the drug effects were executed through the specific inhibition of Ezh2. We further examine the underlying molecular mechanisms by which DZNep exert its effect on NKTL cells using gene expression profiling (GEP). We defined the mechanism by which DZNep induces apoptosis in the NKTL cells, through the de-repression of TNFAIP3/A20, a tumor suppressor gene. In cells with high Ezh2, TNFAIP3/A20 is silenced through the histone methyltransferase activity of Ezh2, resulting in an activation of NF-kB and an oncogenic effect. To conclude, we unravel the oncogenic pathway of Ezh2 in NKTL cells through regulation on TNFAIP3/A20 and NF-kB, and also demonstrated the possibility of targeting Ezh2 using DZNep in NKTL.