Scientists in Singapore report that they have identified a potential new target for treating extranodal natural killer/T-cell lymphoma (NKTL), a rare and aggressive form of cancer.
The production of an enzyme called EZH2 is increased in many cancers, including NKTL. EZH2 typically acts through its catalytic function to repress tumour suppressive genes. Small molecule inhibitors exist which can block the catalytic function of EZH2. However, in the case of NKTL, the oncogenic mechanism of EZH2 is independent of its catalytic function, which means these drugs are not effective in combating the cancer.
Now researchers from the Cancer Science Institute of Singapore (CSI) at the National University of Singapore say they have found for the first time that an enzyme called maternal embryonic leucine zipper kinase (MELK) regulates EZH2.
Writing in the journal Blood, they say it means that EZH2 could be indirectly targeted by targeting MELK.
Senior study author Professor Chng Wee Joo, deputy director of CSI Singapore, said: “MELK serves as a potential biomarker for NKTL and the discovery of the molecular mechanism underlying the disease pathogenesis highlights new targeting routes for the treatment of NKTL.”
First author Dr Li Boheng said: “We sought to gain a clearer understanding of the driving mechanism behind the over-expression of EZH2 in NKTL to develop better therapeutic strategies to treat this disease and improve clinical outcomes.”
The research team found that MELK protein levels in NKTL patients correlated with those of EZH2. They went on to establish that MELK stabilised a previously unknown mechanism of EZH2. They demonstrated that as the EZH2 turnover decreases, it aggravates the resistance to bortezomib treatment in NKTL.
Conversely, when they reduced MELK levels in NKTL cells, they observed an increased sensitivity to bortezomib.
The team says its findings suggest that MELK inhibitors could be developed which, when combined with bortezomib with other chemotherapy regimes, could improve treatment strategies for NKTL in the future.
Li B, Yan J, Phyu T, Fan S, Chung TH, Mustafa NB, Lin B, Wang L, Eichhorn PJA, Goh BC, Ng SB, Kappei D, Chng WJ. (2019) “MELK mediates the stability of EZH2 through site-specific phosphorylation in extranodal natural killer/T-cell lymphoma”, Blood, doi:10.1182/blood.2019000381