Key Points• JAK3-mediated phosphorylation of EZH2 resulted in EZH2 oncogenic function independent of its enzymatic activity.• Targeted inhibition of JAK3 may be a promising treatment in NK/TL through suppressing noncanonical EZH2 activity.The best-understood mechanism by which EZH2 exerts its oncogenic function is through polycomb repressive complex 2 (PRC2)-mediated gene repression, which requires its histone methyltransferase activity. However, small-molecule inhibitors of EZH2 that selectively target its enzymatic activity turn out to be potent only for lymphoma cells with EZH2-activating mutation. Intriguingly, recent discoveries, including ours, have placed EZH2 into the category of transcriptional coactivators and thus raised the possibility of noncanonical signaling pathways. However, it remains unclear how EZH2 switches to this catalytic independent function. In the current study, using natural killer/T-cell lymphoma (NKTL) as a disease model, we found that phosphorylation of EZH2 by JAK3 promotes the dissociation of the PRC2 complex leading to decreased global H3K27me3 levels, while it switches EZH2 to a transcriptional activator, conferring higher proliferative capacity of the affected cells. Gene expression data analysis also suggests that the noncanonical function of EZH2 as a transcriptional activator upregulates a set of genes involved in DNA replication, cell cycle, biosynthesis, stemness, and invasiveness. Consistently, JAK3 inhibitor was able to significantly reduce the growth of NKTL cells, in an EZH2 phosphorylation-dependent manner, whereas various compounds recently developed to inhibit EZH2 methyltransferase activity have no such effect. Thus, pharmacological inhibition of JAK3 activity may provide a promising treatment option for NKTL through the novel mechanism of suppressing noncanonical EZH2 activity. (Blood. 2016;128(7):948-958)

EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which along with other PRC2 components mediates gene expression suppression via the methylation of Histone H3 at lysine 27. Recent studies have revealed a dichotomous role of EZH2 in physiology and in the pathogenesis of cancer. While it plays an essential role in the development of the lymphoid system, its deregulation, whether due to genetic or non-genetic causes, promotes B cell-and T cell-related lymphoma or leukemia. These findings triggered a boom in the development of therapeutic EZH2 inhibitors in recent years. Here, we discuss physiologic and pathogenic function of EZH2 in lymphoid context, various internal causes of EZH2 aberrance and how EZH2 modulates lymphomagenesis through epigenetic silencing, post-translational modifications (PTMs), orchestrating with surrounding tumor micro-environment and associating with RNA or viral partners. We also summarize different strategies to directly inhibit PRC2-EZH2 or to intervene EZH2 upstream signaling.

PurposeThe goal of this study was to investigate the anti-osteoporosis effect of extra virgin olive oil (EVOO) in vivo, and explore its antioxidant, anti-inflammatory properties in Sprague Dawley rats and its anticancer properties in patients.Materials and methodsA total of 120 healthy female Sprague Dawley rats aged 6 months were divided into four groups: 1) sham-operated control (Sham group, n=30); 2) ovariectomized (OVX group, n=30); 3) ovariectomized rats supplemented with EVOO (OVX + Olive, n=30); 4) ovariectomized rats supplemented with estrogen (OVX + E2, n=30). EVOO and estrogen were administered by oral gavage at a dose of 1 mL/100 g weight on a daily basis for 12 consecutive weeks. Twelve weeks later blood samples were obtained to detect the levels of calcium, alkaline phosphatase, phosphorus, interleukin-6 (IL-6), malonyldialdehyde (MDA), and nitrate content. Dual energy X-ray absorptiometer measured bone mineral density (BMD) of ovariectomized Sprague Dawley rats that had been fed olive oil for 3 months. Blood samples from patients, who regularly consumed olive oil over a 1 year period were also used to measure carbohydrate antigen 125, carcino-embryonic antigen, α-fetoprotein, and carbohydrate antigen 19-9 levels. BMD of lumbar spine and left femur was also evaluated by dual energy X-ray absorptiometry.ResultsAnimal experiments showed that EVOO significantly increased BMD and decreased phosphatase, alkaline phosphatase, IL-6, MDA, and nitrate levels. However, it had no significant effect on the Ca2+ level. In clinical follow-up, EVOO also improved patient BMD levels on L3, L4, and left femoral neck, and reduced carbohydrate antigen 125, α-fetoprotein, and carcino-embryonic antigen levels. But it had no significant effect on the carbohydrate antigen 19-9 level.ConclusionEVOO illustrated significant anti-osteoporosis, antioxidant, anti-inflammatory, and anticancer properties in vivo. However, further studies are required to determine the active component(s) responsible for these effects.

This article describes the interplay between the serine/threonine kinase maternal embryonic leucine zipper kinase (MELK) and the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and provides a basis for targeting this enzymatic pathway in mature natural killer/T-cell malignancies.