Ontology highlight
ABSTRACT:
PROVIDER: PRJNA479924 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7475950.fastq.gz | Fastqsanger.gz | |||
| SRR7475960.fastq.gz | Fastqsanger.gz | |||
| SRR7475970.fastq.gz | Fastqsanger.gz | |||
| SRR7475951.fastq.gz | Fastqsanger.gz | |||
| SRR7475961.fastq.gz | Fastqsanger.gz |
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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
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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.
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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.
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Project description:Mutations in LZTR1, a substrate adaptor for cullin 3 (CUL3) ubiquitin ligase complexes1, have been recently associated with Noonan syndrome2,3 and familial Schwannomatosis4-6. Concordantly, we found that Lztr1+/- mice showed craniofacial abnormalities, cardio defects, and premature ageing; whereas loss of LZTR1 in Schwann cells drives their dedifferentiation into proliferating, pro-myelinating cells. We screened for LZTR1 substrates by trapping LZTR1 complexes from intact mammalian cells. In parallel, we analysed changes in the ubiquitin landscape induced by LZTR1 loss of function. RAS proteins emerged as substrates of the LZTR1/CUL3 complex, which inhibits the RAS pathway by ubiquitinating RAS at K170 and triggering its dissociation from the membrane. Disease-associated LZTR1 mutations affect either the LZTR1/CUL3 complex formation, or the interaction with RAS proteins. These results position LZTR1 as a key node in the RAS pathway, loss-of-function of which leads to a human disease.
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