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  • Review Article
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An epigenetic gateway to brain tumor cell identity

Nature Neuroscience volume 19, pages 10–19 (2016)Cite this article

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Abstract

Precise targeting of genetic lesions alone has been insufficient to extend brain tumor patient survival. Brain cancer cells are diverse in their genetic, metabolic and microenvironmental compositions, accounting for their phenotypic heterogeneity and disparate responses to therapy. These factors converge at the level of the epigenome, representing a unified node that can be disrupted by pharmacologic inhibition. Aberrant epigenomes define many childhood and adult brain cancers, as demonstrated by widespread changes to DNA methylation patterns, redistribution of histone marks and disruption of chromatin structure. In this Review, we describe the convergence of genetic, metabolic and microenvironmental factors on mechanisms of epigenetic deregulation in brain cancer. We discuss how aberrant epigenetic pathways identified in brain tumors affect cell identity, cell state and neoplastic transformation, as well as addressing the potential to exploit these alterations as new therapeutic strategies for the treatment of brain cancer.

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Figure 1: The epigenetic gateway to cell identity and neoplastic transformation.
Figure 2: Brain tumors converge on chromatin architecture.
Figure 3: Cellular microenvironment influences epigenetic state of brain tumor cells.
Figure 4: Cellular metabolism influences brain cancer epigenetic state.

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Acknowledgements

We thank D. Schumick (Center of Medical Art and Photography, Cleveland Clinic) for assistance with figure preparation. This work was supported by The Banting Fellowship (S.C.M.), James S. McDonnell Foundation (J.N.R.) and US National Institutes of Health grants: F32 CA189647 (C.G.H.), F30 CA183510 (T.E.M.), T32 GM007250 MSTP (T.E.M.), R35 CA197718 (J.N.R.), CA154130 (J.N.R.), R01 CA169117 (J.N.R.), R01 CA171652 (J.N.R.), R01 NS087913 (J.N.R.) and R01 NS089272 (J.N.R.). M.D.T. is supported by a Canadian Institutes of Health Research Clinician Scientist Phase II award, funds from the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto, and operating funds from the Canadian Institutes of Health Research, the US National Institutes of Health (R01CA159859 and R01CA148699) and the Pediatric Brain Tumor Foundation.

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Authors and Affiliations

  1. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA

    Stephen C Mack, Christopher G Hubert, Tyler E Miller & Jeremy N Rich

  2. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

    Tyler E Miller

  3. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

    Tyler E Miller

  4. Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada

    Michael D Taylor

  5. Division of Neurosurgery, Hospital for Sick Children, Toronto, Ontario, Canada

    Michael D Taylor

  6. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA

    Jeremy N Rich

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Correspondence to Jeremy N Rich.

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Mack, S., Hubert, C., Miller, T. et al. An epigenetic gateway to brain tumor cell identity. Nat Neurosci 19, 10–19 (2016). https://doi.org/10.1038/nn.4190

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