EZH2 non-canonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis [CUT&RUN]

ABSTRACT: Canonically, Enhancer of Zeste Homolog 2 (EZH2) serves as the main catalytic subunit of Polycomb Repressive Complex 2 (PRC2), mediating H3K27me3 deposition and transcriptional repression. Here, we report that, in MLL1-rearranged acute leukemias, EZH2 has additional noncanonical functions by binding the oncoprotein cMyc at its non-PRC2 target sites where EZH2 uses a hidden transactivation domain (TAD) for (co)activator recruitment and gene activation. Canonical (EZH2:PRC2) and noncanonical (EZH2-TAD:cMyc) activities of EZH2 both promote oncogenesis, thus explaining the slow and often ineffective antitumor effects by current catalytic inhibitors of EZH2. To suppress EZH2’s multifaceted activities in cancer, we employed the Proteolysis Targeting Chimera (PROTAC) technology and developed a small-molecule degrader, MS177, which achieved effective, on-target depletion of EZH2 and its interacting partners (i.e., both canonical EZH2:PRC2 and noncanonical EZH2:cMyc complexes). MS177-mediated onco-target degradation is cereblon- and proteasome-dependent. Compared to EZH2 enzymatic inhibitors, MS177 is fast-acting and much more potent in suppressing cancer growth. Overall, this study reveals noncanonical oncogenic functions of EZH2, and presents a highly effective PROTAC for targeting EZH2’s multifaceted tumorigenic actions and a novel and attractive therapeutic strategy for the treatment of EZH2-depdendent cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180446 | GEO | 2021/12/29

REPOSITORIES: GEO