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EZH2 non-canonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis

ABSTRACT: EZH2 non-canonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis

PROVIDER: PRJNA748275 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11806411.fastq.gz	Fastqsanger.gz
	SRR11806412.fastq.gz	Fastqsanger.gz
	SRR11806413.fastq.gz	Fastqsanger.gz
	SRR11806414.fastq.gz	Fastqsanger.gz
	SRR11806415.fastq.gz	Fastqsanger.gz

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

Project description: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.

2021-12-29 | GSE150823 | GEO

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

2021-12-29 | GSE150745 | GEO

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

2021-12-29 | GSE180447 | GEO

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

2021-12-29 | GSE180446 | GEO

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

Project description:EZH2 non-canonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis [RNA-Seq]

| PRJNA633795 | ENA

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

Project description:EZH2 non-canonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis [ChIP-Seq]

| PRJNA633491 | ENA

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

Project description:EZH2 non-canonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis [RNA-seq]

| PRJNA748280 | ENA

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

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

| PRJNA748279 | ENA

EZH2 non-canonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-12-29 | GSE180448 | GEO

EZH2 noncanonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis.

Project description:Canonically, EZH2 serves as the catalytic subunit of PRC2, which mediates H3K27me3 deposition and transcriptional repression. Here, we report that in acute leukaemias, 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. Both canonical (EZH2-PRC2) and noncanonical (EZH2-TAD-cMyc-coactivators) activities of EZH2 promote oncogenesis, which explains the slow and ineffective antitumour effect of inhibitors of the catalytic function of EZH2. To suppress the multifaceted activities of EZH2, we used proteolysis-targeting chimera (PROTAC) to develop a degrader, MS177, which achieved effective, on-target depletion of EZH2 and interacting partners (that is, both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes). Compared with inhibitors of the enzymatic function of EZH2, MS177 is fast-acting and more potent in suppressing cancer growth. 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.

| S-EPMC9710513 | biostudies-literature

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