Researchers at the University of North Carolina (UNC) at Chapel Hill and the UNC Lineberger Comprehensive Cancer Center have uncovered a new role of a chromatin-modulatory enzyme, termed EZH2, during cancer development. They then developed a new therapeutic approach with a potent small-molecule inhibitor of this enzyme.
Their findings are published in the journal Nature Cell Biology in a paper titled, “EZH2 noncanonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis.”
“Canonically, EZH2 serves as the catalytic subunit of PRC2, which mediates H3K27me3 deposition and transcriptional repression,” the researchers wrote. “Here, we report that in acute leukemias, EZH2 has additional noncanonical functions by binding cMyc at non-PRC2 targets and uses a hidden transactivation domain (TAD) for (co)activator recruitment and gene activation.”
UNC researchers collaborated with chemical biologists at the Icahn School of Medicine at Mount Sinai and designed a new small molecule, MS177, based on the proteolysis-targeting chimera (PROTAC) technology. MS177 targets both EZH2 and cMyc and thus inhibits cancer growth.
“EZH2 plays a very important role during cancer progression and is a known target suitable for drug development,” said UNC Lineberger’s Greg Wang, PhD, associate professor of biochemistry and biophysics and pharmacology at the UNC School of Medicine and co-lead author of this research article. “We are amazed by the efficiency of small molecule PROTAC in simultaneously targeting EZH2 and cMyc in cancer cells.”
MS177 achieves on-target effect in cancer cells and exhibits profound tumor-killing effects, the researchers reported. “Compared to the existing enzymatic inhibitors, MS177 is more likely to behave much better for the treatment of patients with acute leukemias. To our knowledge, an agent for dual targeting of EZH2 and cMyc has not been developed before. cMyc is hard to ‘drug,’” Wang said. “MS177 thus represents a promising candidate for treating other cancers depending on the above tumorigenic pathways.”
This study reveals noncanonical oncogenic roles of EZH2, reports a PROTAC for targeting the multifaceted tumorigenic functions of EZH2, and presents an attractive strategy for treating EZH2-dependent cancers.
