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

• Published in: Nature (London) 2014-10, Vol.514 (7521), p.247-251
• Main Authors: De Raedt, Thomas, Beert, Eline, Pasmant, Eric, Luscan, Armelle, Brems, Hilde, Ortonne, Nicolas, Helin, Kristian, Hornick, Jason L., Mautner, Victor, Kehrer-Sawatzki, Hildegard, Clapp, Wade, Bradner, James, Vidaud, Michel, Upadhyaya, Meena, Legius, Eric, Cichowski, Karen
• Format: Article
• Language: English
• Subjects: 13/89; 45/15; 45/23; 45/61; 45/90; 631/67/1059/602; 631/67/581; 631/67/70; 64/60; 96/95; Analysis; Animals; Azepines - pharmacology; Azepines - therapeutic use; Cell Cycle Proteins; Cell Death - drug effects; Chromatin - drug effects; Chromatin - genetics; Chromatin - metabolism; Defects; Disease Models, Animal; Epigenesis, Genetic - drug effects; Epigenetic inheritance; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic transcription; Glioma - drug therapy; Glioma - genetics; Glioma - pathology; Gliomas; Humanities and Social Sciences; Humans; Inactivation; letter; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; Mice; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; multidisciplinary; Mutation; Neoplasm Proteins; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Nerve Sheath Neoplasms - drug therapy; Nerve Sheath Neoplasms - genetics; Nerve Sheath Neoplasms - pathology; Neurofibromin 1 - deficiency; Neurofibromin 1 - genetics; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Polycomb Repressive Complex 2 - deficiency; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Ras genes; ras Proteins - antagonists & inhibitors; ras Proteins - metabolism; Science; Studies; Transcription Factors - antagonists & inhibitors; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Triazoles - pharmacology; Triazoles - therapeutic use; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13561

SUZ12, a component of the PRC2 complex, can also function as a tumour suppressor in certain tumours of the nervous system and melanomas. Interaction of PRC2 with Ras pathway The PRC2 complex, which regulates gene expression through chromatin modification, has been shown to play a pro-tumorigenic role in many tumours. Karen Cichowski and colleagues now show that SUZ12, a component of PRC2, can also function as a tumour suppressor in certain tumours of the nervous system and melanomas. Through deregulation of chromatin and thereby gene expression, SUZ12 loss cooperates with the loss of NF1, another tumour suppressor frequently lost in these tumours types. At the same time, SUZ12 loss renders tumours sensitive to drugs that target bromodomain proteins, which are currently being explored for a number of cancer types. This work reveals an unexpected connection between PRC2 and several components of the Ras pathway, as well as providing possible targets for epigenetic-based therapies. The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types 1 . 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 2 , 3 . 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 4 . 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.