1 Helin Group, BRIC Research Groups, BRIC, Københavns Universitet2 Administration, BRIC Administration, BRIC, Københavns Universitet3 The Danish Stem Cell Center, Faculty of Health and Medical Sciences, Københavns Universitet4 Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School5 Department of Human Genetics, Catholic University Leuven6 Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques7 BRIC Administration, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet8 Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.9 Department of Maxillofacial Surgery, University Medical Centre, Hamburg-Eppendorf, 20246 Hamburg, Germany.10 Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany.11 Herman Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 46202 Indianapolis, Indiana, USA.12 Harvard Medical School13 Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.14 BRIC Administration, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet
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.