EZH2 for inhibition may not cure the disease. One example of a cancer pathway in which EZH2 plays a role is the pRB-E2F pathway. It is downstream from the pRB-E2F pathway, and signals from this pathway lead to EZH2 overexpression. Another important characteristic of EZH2 is that when EZH2 is overexpressed, it can activate genes without forming PRC2. This is an issue because it means the methylation activity of the enzyme is not mediated by complex formation. In breast cancer cells, EZH2 activates genes that promote cell proliferation and survival. It can also activate regulatory genes like c-myc and cyclin D1 by interacting with Wnt signaling factors. Importantly, the mutation of tyrosine 641 in the active SET domain to a number of different amino acids is a common feature of some B-cell lymphomas. Inhibitors Developing an inhibitor of EZH2 and preventing unwanted histone methylation of tumor suppressor genes is a viable area of cancer research. EZH2 inhibitor development has focused on targeting the SET domain active site of the protein. Several inhibitors of EZH2 have been developed as of 2015, including 3-deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, and UNC1999. DZNep DZNep has potential antiviral and anti-cancer properties because it lowers EZH2 levels and induces apoptosis in breast and colon cancer cells. DZNep inhibits the hydrolysis of S-adenosyl-L-homocysteine (SAH), which is a product-based inhibitor of all protein methyltransferases, leading to increased cellular concentrations of SAH which in turn inhibits EZH2. However, DZNep is not specific to EZH2 and also inhibits other DNA methyltransferases. EPZ005687 In 2012, a company called Epizyme revealed EPZ005687, an S-adenosylmethionine (SAM) competitive inhibitor that is more selective than DZNep; it has a 50-fold increase in selectivity for EZH2 compared to EZH1. The drug blocks EZH2 activity by binding to the SET domain active site of the enzyme. EPZ005687 can also inhibit the Y641 and A677 mutants of EZH2, which may be applicable for treating non-Hodgkin's lymphoma. Tazemetostat In 2013, Epizyme began Phase I clinical trials with another EZH2 inhibitor, tazemetostat (EPZ-6438), for patients with B-cell lymphoma. In 2020, tazemetostat, with the tradename Tazverik, gained an FDA accelerated approval for the treatment of metastatic or locally advanced epithelioid sarcoma and an accelerated approval for the treatment of patients with relapsed follicular lymphoma later that year. Sinefungin Sinefungin is another SAM-competitive inhibitor, however, like DZNep, it is not specific to EZH2. It works by binding in the cofactor binding