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| Status |
Public on Dec 29, 2021 |
| Title |
EZH2 non-canonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis [ChIP-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
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.
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| Overall design |
Use ChIP-seq to examine the genome-wide binding of EZH2 or H3K27me3 in EOL-1 or MV4;11 cells, treated with either DMSO, C24 (an EZH2 inhibitor) or MS177 (the EZH2 PROTAC/degrader); a fraction of Drosophila chromatin was added as spike-in control, probed with the Drosophila specific H2Av antibody, for accessing relative binding of EZH2 or H3K27me3 post-treatment of different compounds.
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| Contributor(s) |
Wang J, Wang G |
| Citation(s) |
35210568 |
| Submission date |
May 18, 2020 |
| Last update date |
Mar 30, 2022 |
| Contact name |
Jun Wang |
| E-mail(s) |
jun113@email.unc.edu
|
| Phone |
9199665953
|
| Organization name |
UNC Lineberger Comprehensive Cancer Center
|
| Lab |
Greg Wang lab
|
| Street address |
450 West Drive, CB 7295, UNC cancer center, room 31-331
|
| City |
Chapel Hill |
| State/province |
North Carolina |
| ZIP/Postal code |
27599 |
| Country |
USA |
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| Platforms (1) |
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| Samples (14)
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| This SubSeries is part of SuperSeries: |
| GSE180448 |
EZH2 non-canonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis |
|
| Relations |
| BioProject |
PRJNA633491 |
| SRA |
SRP262127 |
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