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RNA-seq to profile the transcriptome changes induced by the EZH2 degrader MS1943

ABSTRACT: RNA-seq to profile the transcriptome changes induced by the EZH2 degrader MS1943

PROVIDER: PRJNA540486 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8992061_1.fastq.gz	Fastqsanger.gz
	SRR8992061_2.fastq.gz	Fastqsanger.gz
	SRR8992062_1.fastq.gz	Fastqsanger.gz
	SRR8992062_2.fastq.gz	Fastqsanger.gz
	SRR8992063_1.fastq.gz	Fastqsanger.gz

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

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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RNA-seq to profile the transcriptome changes induced by the EZH2 degrader MS1943

Project description:To gain mechanistic insights into how MS1943 induces cell death, MDA-MB-468 cells were treated with 5 µM of MS1943 or DMSO control and changes of gene expression were assessed after 3 days of treatment. Interestingly, MS1943-treated cells were characterized by a unique set of deregulated genes that could readily separate them from control cells. We identified 8,730 significant differentially expressed genes with a false discovery rate (FDR) at 5%, in which 2,120 genes have an absolute log fold change above 1. We next performed gene set enrichment analyses (GSEA) that capture pathways perturbed towards both directions simultaneously using the 24,448 ranked genes identified in our dataset and annotated in ENSEMBL (version 94) against the KEGG pathways and the hallmarks gene set collection (MSigDB V6.2). Induction of the unfolded protein response (UPR) / endoplasmic reticulum (ER)-stress pathway was commonly identified using both types of analyses and we therefore decided to pursue this further.

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

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

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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]

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