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PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies [ChIP-seq]

ABSTRACT: The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types1. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer2,3. Here we provide genomic, cellular, and mouse mod- elling data demonstrating that the polycomb group gene SUZ12 func- tions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras4. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhib- itors. Collectively, these studies not only reveal an unexpected con- nection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE62499 | GEO | 2014/10/21

SECONDARY ACCESSION(S): PRJNA264623

REPOSITORIES: GEO

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PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies [expression array]

Project description:The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types1. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, sug- gesting that this complex plays a dichotomous and poorly understood role in cancer2,3. Here we provide genomic, cellular, and mouse mod- elling data demonstrating that the polycomb group gene SUZ12 func- tions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras4. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhib- itors. Collectively, these studies not only reveal an unexpected con- nection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers. 9 samples in triplicates, 3x LacZ control, 3x SUZ12 over expression, 3x JQ1 treatment

2014-10-21 | E-GEOD-62500 | biostudies-arrayexpress

PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies [ChIP-seq]

Project description:The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types1. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer2,3. Here we provide genomic, cellular, and mouse mod- elling data demonstrating that the polycomb group gene SUZ12 func- tions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras4. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhib- itors. Collectively, these studies not only reveal an unexpected con- nection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers. 2x3 samples (DMSO and PDJQ treated; WCL, BRD4 and H3K27Ac pulldown)

2014-10-21 | E-GEOD-62499 | biostudies-arrayexpress

PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies [expression array]

2014-10-21 | GSE62500 | GEO

SUZ12 and NF1 loss cooperate to enhance Ras transcriptional output and sensitize cancers to epigenetic therapies

Project description:The polycomb repressive complex 2 (PRC2) plays an oncogenic role in several cancers. However, loss-of-function mutations in PRC2 components have been detected in a subset of hematopoietic malignancies, suggesting that different epigenetic landscapes are required in different tumor types. In this study we provide genomic, cellular, and mouse modeling data to demonstrate that loss-of-function mutations in the polycomb gene, SUZ12, and NF1 cooperate in peripheral nervous system tumors, glioblastomas, and melanomas. NF1 encodes a Ras GTPase-activating protein and its loss triggers moderate levels of Ras activation. We show that SUZ12-loss enhances the effects of NF1 mutations, in part, by amplifying Ras transcriptional signatures. Moreover, SUZ12-loss triggers an epigenetic switch that confers sensitivity to combined bromodomain and MEK inhibitors in vivo. Collectively these studies demonstrate an unexpected role for polycomb group genes in NF1 mutant tumors and reveal an epigenetic-based therapeutic strategy that may be exploited for a variety of cancers. 9 samples in triplicates, 3x LacZ control, 3x SUZ12 over expression, 3x JQ1 treatment

2014-07-01 | E-GEOD-52777 | biostudies-arrayexpress

Oncogenomics of Malignant Peripheral Nerve Sheath Tumors

Project description:<p>Malignant peripheral nerve sheath tumors (MPNSTs) are a group of highly aggressive soft tissue sarcomas that may occur sporadically, in association with neurofibromatosis type I (NF1-associated), or after radiotherapy (RT-associated). We utilized comprehensive genomic approaches and identified recurrent loss-of-function somatic alterations in the Polycomb repressive complex 2 (PRC2) core components EED or SUZ12. Genetic loss of either of these two genes results in complete loss of H3K27me3 and aberrant transcriptional programming in the affected tumors.</p>

| phs000792 | dbGaP

Loss of PRC2 enforces a mesenchymal neural crest stem cell phenotype in NF1-deficient cancer through activation of core transcription factors [single-cell RNA-seq]

Project description:Genetic alterations that result in the dysregulation of polycomb repressive complex 2 (PRC2) are common features of multiple cancer types. Loss-of-function mutations in the PRC2 genes, SUZ12 or EED, occur at high frequency in malignant peripheral nerve sheath tumors (MPNST), a clinically aggressive sarcoma that arises from NF1-deficient Schwann cells. To define the oncogenic mechanisms mediated by PRC2 loss, we used engineered MPNST model systems that dynamically reassemble a competent PRC2 coupled with single cell sequencing from clinical samples to evaluate the transcriptomic and epigenetic consequences of PRC2 loss. We discovered a two-pronged oncogenic process; first, PRC2 loss leads to remodeling of bivalent chromatin and the enhancer landscape of the tumor cell. These epigenetic changes result in the upregulation of developmentally regulated transcription factors, including FOXC1, which enforce a transcriptional circuit that is a core vulnerability of the cell. Second, PRC2 loss reduces type I interferon signaling and antigen presentation as a downstream consequence of hyperactivated Ras signaling and its crosstalk with STAT and IRF transcription factors. Mapping of the transcriptional program of these PRC2-deficient tumor cells onto a constructed developmental trajectory of the developing neural crest stem cell revealed that changes induced by PRC2 loss enforced a cellular profile characteristic of a primitive mesenchymal neural crest stem cell.

2022-09-20 | GSE183308 | GEO

Loss of PRC2 enforces a mesenchymal neural crest stem cell phenotype in NF1-deficient cancer through activation of core transcription factors [RNA-seq]

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Loss of PRC2 enforces a mesenchymal neural crest stem cell phenotype in NF1-deficient cancer through activation of core transcription factors [ChIP-seq]

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Loss of PRC2 enforces a mesenchymal neural crest stem cell phenotype in NF1-deficient cancer through activation of core transcription factors [ATAC-seq]

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Loss of PRC2 enforces a mesenchymal neural crest stem cell phenotype in NF1-deficient cancer through activation of core transcription factors [CUT&RUN]

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