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

Nature. 2014 Oct 9;514(7521):247-51. doi: 10.1038/nature13561. Epub 2014 Aug 13.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Azepines / pharmacology
  • Azepines / therapeutic use
  • Cell Cycle Proteins
  • Cell Death / drug effects
  • Chromatin / drug effects
  • Chromatin / genetics
  • Chromatin / metabolism
  • Disease Models, Animal
  • Epigenesis, Genetic / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioma / drug therapy
  • Glioma / genetics
  • Glioma / pathology
  • Humans
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Melanoma / pathology
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • 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
  • 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
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / metabolism*

Substances

  • (+)-JQ1 compound
  • Azepines
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Chromatin
  • Neurofibromin 1
  • Nuclear Proteins
  • SUZ12 protein, human
  • Suz12 protein, mouse
  • Transcription Factors
  • Triazoles
  • Tumor Suppressor Proteins
  • Polycomb Repressive Complex 2
  • Mitogen-Activated Protein Kinase Kinases
  • ras Proteins

Associated data

  • GEO/GSE52777