The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumor types. However, loss-of-function mutations in PRC2 components occur in a subset of hematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer. Our genomic, cellular, and mouse modeling data demonstrates that the polycomb group gene SUZ12 functions as tumor suppressor in PNS tumors, glioblastomas, and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein and its loss drives cancer by activating Ras. We show that SUZ12-loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription. 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.

Citation Format: Thomas De Raedt, Eline Beert, Eric Pasmant, Armelle Luscan, Hilde Brems, Nicolas Ortonne, Kristian Helin, Victor Mautner, Hildegard Kehrer-Sawatski, Wade Clapp, James Bradner, Meena Upadhyaya, Michel Vidaud, Eric Legius, Karen Cichowski. PRC2 loss amplifies Ras-driven transcription and sensitizes cancers to bromodomain inhibitor-based combination therapies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-79. doi:10.1158/1538-7445.AM2014-LB-79