DZNep is a PRC inhibitor that inhibits S adenosylhomocystein

DZNep is a PRC2 inhibitor that inhibits S-adenosylhomocysteine hydrolase, resulting in cellular accumulation of S-adenosylhomocysteine. S-adenosylhomocysteine is a competitive inhibitor of methyl donor for methyltransferases [38]. DZNep targets EZH2 by reduction in the level of the enzyme H3K27me3 and by induction of apoptosis in various tumor cells [39], [40]. We found that DZNep significantly reduced EZH2, inhibited growth of NK tumor cells, and induced apoptosis of tumor cells. Currently, EZH2 inhibitors are being investigated in clinical trials for B-cell lymphomas [41], Therefore, targeting EZH2 may have potential therapeutic value in clinical strategies of this lymphoma.
Lung cancer is the leading cause of cancer-related death worldwide, and its prognosis remains poor . However, the elucidation of its genetic pathogenesis has paved the way for a new era in the management of lung cancer. Genetic alterations in epidermal growth factor receptor () and anaplastic lymphoma kinase are representative driver oncogenes in non-small cell lung cancer (NSCLC). Mutations or rearrangement in these oncogenic drivers lead to their constitutive activation and promote tumor cell growth via transducing pathways, such as the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase, phosphatidylinositol 3-kinase/AKT, and signal transducer and activator of transcription pathways . Specific inhibitors, such as gefitinib and crizotinib, have dramatically prolonged the survival of patients with oncogene-driven lung cancer , . In addition to these driver oncogenes, the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has been recognized as an important mechanism underlying the immune escape of tumor cells from T cells : the interaction between PD-1 and PD-L1 or PD-L2 attenuates the T cell activity, which results in the downregulation of the immune response against cancer cells . The inhibition of such interactions with PD-1–blocking or PD-L1–blocking BIX 02565 induces an immune response in T cells against cancer cells . Thus, immune-checkpoint molecules have attracted a great deal of attention due to their excellent targetability , , , and PD-L1 has been shown to be predictive of the response to immune-checkpoint inhibitors . However, intrinsic or acquired resistance to immune-checkpoint inhibitors remains a critical concern. Although some mechanisms involving the phosphatidylinositol 3-kinase gamma and Janus kinase families have been proposed, other resistance mechanisms have yet to be elucidated , . The deregulation of epigenetics, including DNA methylation, histone modifications, and noncoding RNA, is also reported to be involved in the pathogenesis of various types of cancer, including lung cancer . Histone methylation is a particularly important process that mainly regulates the transcription of the genes associated with the pathogenesis of cancer . Among histone methyltransferases, enhancer of zeste homolog 2 (EZH2) methylates lysine residue 27 on histone H3, resulting in transcriptional repression . Several reports have shown the deep involvement of EZH2 in the proliferation and survival of various types of cancer, including lung cancer, bladder cancer, and melanoma , , , . Several EZH2 inhibitors have been developed and are currently under evaluation in clinical trials , . For instance, Zhang and colleagues showed that the EZH2 inhibitor JQEZ5 exerted antitumor effects against EZH2-driven lung adenocarcinomas in vivo. In addition, other preclinical data showed that the growth of SCLC could be suppressed by the knockdown of EZH2 . EZH2 has therefore attracted much attention because of its potential targetability for lung cancer. Furthermore, a recent report demonstrated the important role of EZH2 in controlling the mechanisms of adaptive resistance to tumor immunotherapy in human skin cutaneous melanoma: inactivation of EZH2 reversed resistance to cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or interleukin (IL)-2 immunotherapy and synergized with anti-CTLA-4 and IL-2 immunotherapy, resulting in the suppression of melanoma proliferation . These effects were reported to depend on PD-L1 downregulation in melanoma cells, and we therefore hypothesized that there might be a possible correlation between the PD-L1 and EZH2 expression. However, the relationship between the EZH2 and PD-L1 expression in lung cancer has yet to be clarified.