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Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader

ABSTRACT: Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader

PROVIDER: PRJNA886651 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21786505_1.fastq.gz	Fastqsanger.gz
	SRR21786505_2.fastq.gz	Fastqsanger.gz
	SRR21786506_1.fastq.gz	Fastqsanger.gz
	SRR21786506_2.fastq.gz	Fastqsanger.gz
	SRR21786507_1.fastq.gz	Fastqsanger.gz

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Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader [RNA-seq]

Project description:Multiple myeloma (MM) is the second most common hematological malignancy with poor prognosis. Enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) for transcriptional repression. EZH2 have been implicated in numerous hematological malignancies, including MM. However, noncanonical functions of EZH2 in MM tumorigenesis are not well understood. Here, we uncovered a noncanonical function of EZH2 in MM malignancy. In addition to the PRC2-mediated and H3K27me3-dependent canonical function, EZH2 interacts with cMyc and co-localizes with gene activation markers, promoting MM tumorigenesis in a PRC2- and H3K27me3-independent manner. Both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes can be effectively depleted in MM cells by MS177, an EZH2 degrader we reported previously, leading to profound activation of EZH2-PRC2-associated genes and suppression of EZH2-cMyc oncogenic nodes. The MS177-induced degradation of both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes also reactivated immune response genes in MM cells. Phenotypically, targeting of EZH2’s both canonical and noncanonical functions by MS177 effectively suppressed the proliferation of MM cells both in vitro and in vivo. Collectively, this study uncovers a new noncanonical function of EZH2 in MM tumorigenesis and provides a novel therapeutic strategy, pharmacological degradation of EZH2, for treating EZH2-dependent MM.

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Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader [CUT&RUN]

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Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader [CUT&RUN]

Project description:Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader [CUT&RUN]

| PRJNA886657 | ENA

Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader [RNA-seq]

Project description:Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader [RNA-seq]

| PRJNA886658 | ENA

Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader

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

2023-01-25 | GSE214669 | GEO

MMSET alters EZH2 Binding in Myeloma Cells

Project description:We investigated EZH2 binding in the presence and absence of MMSET protein. MMSET overexpression in t(4;14)+ myeloma leads to global loss of H3K27 methylation and redistribution of EZH2 binding throughout the genome ChIP-seq for EZH2 in two cell types

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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.

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

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