PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies

TY - JOUR

T1 - PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies

AU - De Raedt, Thomas

AU - Beert, Eline

AU - Pasmant, Eric

AU - Luscan, Armelle

AU - Brems, Hilde

AU - Ortonne, Nicolas

AU - Helin, Kristian

AU - Hornick, Jason L

AU - Mautner, Victor

AU - Kehrer-Sawatzki, Hildegard

AU - Clapp, Wade

AU - Bradner, James

AU - Vidaud, Michel

AU - Upadhyaya, Meena

AU - Legius, Eric

AU - Cichowski, Karen

PY - 2014/10/9

Y1 - 2014/10/9

N2 - The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types. 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 cancer. Here we provide genomic, cellular, and mouse modelling data demonstrating that the polycomb group gene SUZ12 functions 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 Ras. 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 inhibitors. Collectively, these studies not only reveal an unexpected connection 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.

AB - The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types. 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 cancer. Here we provide genomic, cellular, and mouse modelling data demonstrating that the polycomb group gene SUZ12 functions 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 Ras. 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 inhibitors. Collectively, these studies not only reveal an unexpected connection 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.

U2 - 10.1038/nature13561

DO - 10.1038/nature13561

M3 - Journal article

C2 - 25119042

SN - 0028-0836

JO - Nature

JF - Nature

ER -