PRC2 Subunits Are Tumor Suppressors in NF1-Deficient Solid Tumors

Genetic loss of neurofibromin 1 (NF1) underlies neurofibromatosis type 1, a familial cancer predisposition syndrome characterized by the growth of nervous system tumors. Patients harboring a germline 17q microdeletion causing the loss of NF1 and 13 other genes have a dramatic increase in the number of benign neurofibromas and a much higher incidence of malignant peripheral nerve sheath tumors (MPNST), suggesting that a cooperating tumor suppressor lies within this region. De Raedt, Beert, Pasmant, and colleagues performed comparative genomic hybridization on 51 NF1-deficient MPNSTs and found heterozygous or homozygous deletions or mutations of SUZ12, a gene within the microdeletion region that encodes a Polycomb repressive complex 2 (PRC2) subunit, in both microdeletion and non-microdeletion MPNSTs. Notably, another PRC2 gene, EED, was recurrently deleted or mutated in MPNSTs, further implicating PRC2 inactivation in MPNST development. Consistent with these findings, reexpression of SUZ12 suppressed the growth of NF1-deficient but not NF1–wild-type tumor cells, and deletion of Suz12 in cis with Nf1 accelerated tumor formation and decreased survival in mice. Given that loss of H3K27 trimethylation caused by PRC2 inactivation can increase H3K27 acetylation, which recruits bromodomain proteins like BRD4, the authors hypothesized that SUZ12 loss might confer sensitivity to bromodomain inhibitors. Indeed, SUZ12-mutant MPNST cells were more sensitive to JQ1 than SUZ12–wild-type cells. However, JQ1 had only cytostatic effects in SUZ12-mutant MPNST cells, whereas the combination of JQ1 and a MEK inhibitor was cytotoxic and induced significant tumor regression in vivo. JQ1 suppressed RAS-driven transcription in part by displacing BRD4 from RAS signature genes, but JQ1 and the MEK inhibitor suppressed RAS signature gene expression more potently together than either agent alone. In addition to identifying an epigenetically driven link between PRC2 and RAS in the development of NF1-deficient tumors, these findings provide a rationale for evaluation of BRD4 and MEK inhibitor combination therapy in patients with NF1-deficient tumors.

De Raedt T, Beert E, Psamant E, Luscan A, Brems H, Ortonne N, et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 2014 Aug 13 [Epub ahead of print].

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