An epigenetic gateway to brain tumor cell identity

Nature Neuroscience

Volumn 19, Issue 1, 2015, Pages 10-19

  Mack, Stephen C ^a   Hubert, Christopher G ^a   Miller, Tyler E ^a,b   Taylor, Michael D ^c   Rich, Jeremy N ^a,b  

^a LERNER RESEARCH INSTITUTE   (United States)

^b CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c HOSPITAL FOR SICK CHILDREN   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

HISTONE; MYC PROTEIN; OLIGODENDROCYTE TRANSCRIPTION FACTOR 2; TRANSCRIPTION FACTOR SOX2;

BRAIN CANCER; BRAIN CELL; BRAIN TUMOR; CANCER GENETICS; CANCER STEM CELL; CELL HYPOXIA; CELL METABOLISM; CHILDHOOD CANCER; CHROMATIN; CYTOARCHITECTURE; DNA METHYLATION; ENDOTHELIUM CELL; EPENDYMOMA; EPIGENETICS; GENE CONTROL; GENE MUTATION; GENETIC REGULATION; GLIOBLASTOMA; HISTONE MODIFICATION; HUMAN; MALIGNANT TRANSFORMATION; MEDULLOBLASTOMA; NEURAL STEM CELL; NONHUMAN; NUCLEAR REPROGRAMMING; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; REVIEW; STEM CELL NICHE; TUMOR CELL; TUMOR MICROENVIRONMENT; ADULT; ANIMAL; BRAIN NEOPLASMS; CHILD; GENETIC EPIGENESIS; GENETICS; METABOLISM;

ADULT; ANIMALS; BRAIN NEOPLASMS; CHILD; EPIGENESIS, GENETIC; HUMANS; NEOPLASTIC STEM CELLS;

EID: 84953731467     PISSN: 10976256     EISSN: 15461726     Source Type: Journal    
DOI: 10.1038/nn.4190     Document Type: Review

References (150)

1. Louis D.N., et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114, 97-109 (2007).
2. Lawrence M.S., et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 505, 495-501 (2014).
3. Bettegowda C., et al. Exomic sequencing of four rare central nervous system tumor types. Oncotarget. 4, 572-583 (2013).
4. Jiao Y., et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget. 3, 709-722 (2012).
5. Parsons D.W., et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 321, 1807-1812 (2008).
6. Parsons D.W., et al. The genetic landscape of the childhood cancer medulloblastoma. Science. 331, 435-439 (2011).
7. Yan H., et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765-773 (2009).
8. Brennan C.W., et al. TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell. 155, 462-477 (2013).
9. Schwartzentruber J., et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 482, 226-231 (2012).
10. Bjerke L., et al. Histone H3.3. mutations drive pediatric glioblastoma through upregulation of MYCN. Cancer Discov. 3, 512-519 (2013).
11. Dubuc A.M., et al. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathol. 125, 373-384 (2013).
12. Northcott P.A., et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature. 511, 428-434 (2014).
13. Northcott P.A., et al. Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat. Genet. 41, 465-472 (2009).
14. Northcott P.A., et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 488, 49-56 (2012).
15. Hovestadt V., et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature. 510, 537-541 (2014).
16. Jones D.T., et al. Dissecting the genomic complexity underlying medulloblastoma. Nature. 488, 100-105 (2012).
17. Pugh T.J., et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature. 488, 106-110 (2012).
18. Rausch T., et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell. 148, 59-71 (2012).
19. Mack S.C., et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature. 506, 445-450 (2014).
20. Lee R.S., et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J. Clin. Invest. 122, 2983-2988 (2012).
21. Torchia J., et al. Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis. Lancet Oncol. 16, 569-582 (2015).
22. Buczkowicz P., et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat. Genet. 46, 451-456 (2014).
23. Fontebasso A.M., et al. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat. Genet. 46, 462-466 (2014).
24. Buczkowicz P., Bartels U., Bouffet E., Becher O., & Hawkins C. Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications. Acta Neuropathol. 128, 573-581 (2014).
25. Taylor K.R., et al. Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat. Genet. 46, 457-461 (2014).
26. Wu G., et al. St. Jude Childrens Research Hospital-Washington University Pediatric Cancer Genome Project. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251-253 (2012).
27. Wu G., et al. St. Jude Childrens Research Hospital-Washington University Pediatric Cancer Genome Project. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat. Genet. 46, 444-450 (2014).
28. Kleinman C.L., et al. Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nat. Genet. 46, 39-44 (2014).
29. Calabrese C., et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 11, 69-82 (2007).
30. Gordan J.D., Bertout J.A., Hu C.J., Diehl J.A., & Simon M.C. HIF-2α promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 11, 335-347 (2007).
31. Li Z., et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 15, 501-513 (2009).
32. Fukumura D., et al. Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res. 61, 6020-6024 (2001).
33. Comerford S.A., et al. Acetate dependence of tumors. Cell. 159, 1591-1602 (2014).
34. Eyler C.E., et al. Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2. Cell. 146, 53-66 (2011).
35. Hjelmeland A.B., et al. Acidic stress promotes a glioma stem cell phenotype. Cell Death Differ. 18, 829-840 (2011).
36. Charles N., et al. Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell. 6, 141-152 (2010).
37. Koivunen P., et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 483, 484-488 (2012).
38. Lu C., et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 483, 474-478 (2012).
39. Turcan S., et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 483, 479-483 (2012).
40. Slongo M.L., et al. Functional VEGF and VEGF receptors are expressed in human medulloblastomas. Neuro Oncol. 9, 384-392 (2007).
41. Mutoh T., Sanosaka T., Ito K., & Nakashima K. Oxygen levels epigenetically regulate fate switching of neural precursor cells via hypoxia-inducible factor 1α-notch signal interaction in the developing brain. Stem Cells. 30, 561-569 (2012).
42. Hanahan D., & Weinberg R.A. Hallmarks of cancer: the next generation. Cell. 144, 646-674 (2011).
43. Takahashi K., & Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 126, 663-676 (2006).
44. Vierbuchen T., et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 463, 1035-1041 (2010).
45. Han D.W., et al. Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell. 10, 465-472 (2012).
46. Najm F.J., et al. Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells. Nat. Biotechnol. 31, 426-433 (2013).
47. Gangemi R.M., et al. SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity. Stem Cells. 27, 40-48 (2009).
48. Suvà M.L., et al. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell. 157, 580-594 (2014).
49. Sarkar A., & Hochedlinger K. The Sox family of transcription factors: versatile regulators of stem and progenitor cell fate. Cell Stem Cell. 12, 15-30 (2013).
50. Suvà M.L., Riggi N., & Bernstein B.E. Epigenetic reprogramming in cancer. Science. 339, 1567-1570 (2013).
51. Stricker S.H., et al. Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner. Genes Dev. 27, 654-669 (2013).
52. Friedmann-Morvinski D., et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science. 338, 1080-1084 (2012).
53. Patel A.P., et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 344, 1396-1401 (2014).
54. Meyer M., et al. Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity. Proc. Natl. Acad. Sci. USA. 112, 851-856 (2015).
55. Polak P., et al. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature. 518, 360-364 (2015).
56. Schuster-Böckler B., & Lehner B. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature. 488, 504-507 (2012).
57. Liu L., De S., & Michor F. DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes. Nat. Commun. 4, 1502 (2013).
58. Black J.C., et al. KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell. 154, 541-555 (2013).
59. Ben-Porath I., et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet. 40, 499-507 (2008).
60. Easwaran H., et al. A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Res. 22, 837-849 (2012).
61. Kim J., et al. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell. 143, 313-324 (2010).
62. Corces-Zimmerman M.R., Hong W.J., Weissman I.L., Medeiros B.C., & Majeti R. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc. Natl. Acad. Sci. USA. 111, 2548-2553 (2014).
63. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 489, 57-74 (2012).
64. Kundaje A., et al. Roadmap Epigenomics Consortium. Integrative analysis of 111 reference human epigenomes. Nature. 518, 317-330 (2015).
65. Tessarz P., & Kouzarides T. Histone core modifications regulating nucleosome structure and dynamics. Nat. Rev. Mol. Cell Biol. 15, 703-708 (2014).
66. Hodis E., et al. A landscape of driver mutations in melanoma. Cell. 150, 251-263 (2012).
67. Imielinski M., et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 150, 1107-1120 (2012).
68. Pugh T.J., et al. The genetic landscape of high-risk neuroblastoma. Nat. Genet. 45, 279-284 (2013).
69. Robinson G., et al. Novel mutations target distinct subgroups of medulloblastoma. Nature. 488, 43-48 (2012).
70. Zhang J., et al. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature. 481, 329-334 (2012).
71. Zhang J., et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 481, 157-163 (2012).
72. Hasselblatt M., et al. High-resolution genomic analysis suggests the absence of recurrent genomic alterations other than SMARCB1 aberrations in atypical teratoid/rhabdoid tumors. Genes Chromosom. Cancer. 52, 185-190 (2013).
73. Ho L., et al. An embryonic stem cell chromatin remodeling complex, esBAF, is an essential component of the core pluripotency transcriptional network. Proc. Natl. Acad. Sci. USA. 106, 5187-5191 (2009).
74. Roberts C.W., Galusha S.A., McMenamin M.E., Fletcher C.D., & Orkin S.H. Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice. Proc. Natl. Acad. Sci. USA. 97, 13796-13800 (2000).
75. Klochendler-Yeivin A., et al. The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression. EMBO Rep. 1, 500-506 (2000).
76. Guidi C.J., et al. Disruption of Ini1 leads to peri-implantation lethality and tumorigenesis in mice. Mol. Cell. Biol. 21, 3598-3603 (2001).
77. Roberts C.W., Leroux M.M., Fleming M.D., & Orkin S.H. Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Cancer Cell. 2, 415-425 (2002).
78. Eroglu E., et al. SWI/SNF complex prevents lineage reversion and induces temporal patterning in neural stem cells. Cell. 156, 1259-1273 (2014).
79. Parker M., et al. C11orf95-RELA fusions drive oncogenic NF-?B signalling in ependymoma. Nature. 506, 451-455 (2014).
80. Johnson R.A., et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature. 466, 632-636 (2010).
81. Witt H., et al. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell. 20, 143-157 (2011).
82. Li M., et al. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell. 16, 533-546 (2009).
83. Sin-Chan P., & Huang A. DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors. Expert Opin. Ther. Targets. 18, 1103-1107 (2014).
84. Khuong-Quang D.A., et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 124, 439-447 (2012).
85. Bender S., et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell. 24, 660-672 (2013).
86. Chan K.M., et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 27, 985-990 (2013).
87. Sturm D., et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 22, 425-437 (2012).
88. Lewis P.W., et al. Inhibition of PRC2 activity by a gain-of-function H3 H3 mutation found in pediatric glioblastoma. Science. 340, 857-861 (2013).
89. Funato K., Major T., Lewis P.W., Allis C.D., & Tabar V. Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science. 346, 1529-1533 (2014).
90. Heaphy C.M., et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science. 333, 425 (2011).
91. Fontebasso A.M., et al. Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol. 125, 659-669 (2013).
92. Hnisz D., et al. Super-enhancers in the control of cell identity and disease. Cell. 155, 934-947 (2013).
93. Mansour M.R., et al. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science. 346, 1373-1377 (2014).
94. Killela P.J., et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl. Acad. Sci. USA. 110, 6021-6026 (2013).
95. Remke M., et al. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. Acta Neuropathol. 126, 917-929 (2013).
96. Bell R.J., et al. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science. 348, 1036-1039 (2015).
97. Zardo G., et al. Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Nat. Genet. 32, 453-458 (2002).
98. Noushmehr H., et al. Cancer Genome Atlas Research Network. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 17, 510-522 (2010).
99. Rideout W.M. III, Coetzee G.A., Olumi A.F., & Jones P.A. 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science. 249, 1288-1290 (1990).
100. Tubio J.M., et al. ICGC Breast Cancer Group; ICGC Bone Cancer Group; ICGC Prostate Cancer Group. Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science. 345, 1251343 (2014).
101. Venkatesh H.S., et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell. 161, 803-816 (2015).
102. Young R.A. Control of the embryonic stem cell state. Cell. 144, 940-954 (2011).
103. Mohyeldin A., Garzón-Muvdi T., & Quiñones-Hinojosa A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell. 7, 150-161 (2010).
104. Keith B., Johnson R.S., & Simon M.C. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer. 12, 9-22 (2012).
105. Seidel S., et al. A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain. 133, 983-995 (2010).
106. Soeda A., et al. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene. 28, 3949-3959 (2009).
107. Wang J., et al. c-Myc is required for maintenance of glioma cancer stem cells. PLoS One 3, e3769 (2008).
108. Heddleston J.M., et al. Hypoxia-induced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential. Cell Death Differ. 19, 428-439 (2012).
109. Lu Y., Chu A., Turker M.S., & Glazer P.M. Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter. Mol. Cell. Biol. 31, 3339-3350 (2011).
110. Shahrzad S., Bertrand K., Minhas K., & Coomber B.L. Induction of DNA hypomethylation by tumor hypoxia. Epigenetics. 2, 119-125 (2007).
111. Gatenby R.A., & Gillies R.J. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer. 4, 891-899 (2004).
112. Chiche J., Brahimi-Horn M.C., & Pouysségur J. Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J. Cell. Mol. Med. 14, 771-794 (2010).
113. McBrian M.A., et al. Histone acetylation regulates intracellular pH. Mol. Cell. 49, 310-321 (2013).
114. Bao S., et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 66, 7843-7848 (2006).
115. Christensen K., Schrøder H.D., & Kristensen B.W. CD133+ niches and single cells in glioblastoma have different phenotypes. J. Neurooncol. 104, 129-143 (2011).
116. Hambardzumyan D., et al. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 22, 436-448 (2008).
117. Bao S., et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444, 756-760 (2006).
118. Pietras A., et al. Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth. Cell Stem Cell. 14, 357-369 (2014).
119. Condeelis J., & Pollard J.W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 124, 263-266 (2006).
120. Pyonteck S.M., et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264-1272 (2013).
121. Zhou W., et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-Associated macrophages and promotes malignant growth. Nat. Cell Biol. 17, 170-182 (2015).
122. Bhat K.P., et al. Mesenchymal differentiation mediated by NF-?B promotes radiation resistance in glioblastoma. Cancer Cell. 24, 331-346 (2013).
123. Ortiz B., et al. Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis. Proc. Natl. Acad. Sci. USA. 111, 8149-8154 (2014).
124. Zhu T.S., et al. Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res. 71, 6061-6072 (2011).
125. Lobov I.B., et al. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc. Natl. Acad. Sci. USA. 104, 3219-3224 (2007).
126. Giancotti F.G. Mechanisms governing metastatic dormancy and reactivation. Cell. 155, 750-764 (2013).
127. Contrino J., Hair G., Kreutzer D.L., & Rickles F.R. In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease. Nat. Med. 2, 209-215 (1996).
128. Ghajar C.M., et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807-817 (2013).
129. Magnus N., et al. Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations. Proc. Natl. Acad. Sci. USA. 111, 3544-3549 (2014).
130. Lee J.V., et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306-319 (2014).
131. Wellen K.E., et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 324, 1076-1080 (2009).
132. Mashimo T., et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell. 159, 1603-1614 (2014).
133. Wise D.R., et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl. Acad. Sci. USA. 105, 18782-18787 (2008).
134. Cascón A., et al. Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene. J. Natl. Cancer Inst. 107, djv053 (2015).
135. Hao H.X., et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 325, 1139-1142 (2009).
136. Rohle D., et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 340, 626-630 (2013).
137. Flavahan W.A., et al. Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nat. Neurosci. 16, 1373-1382 (2013).
138. Korkola J.E., et al. Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors. Cancer Res. 66, 820-827 (2006).
139. Levasseur D.N., Wang J., Dorschner M.O., Stamatoyannopoulos J.A., & Orkin S.H. Oct4 dependence of chromatin structure within the extended Nanog locus in ES cells. Genes Dev. 22, 575-580 (2008).
140. Kaelin W.G. Jr., & McKnight S.L. Influence of metabolism on epigenetics and disease. Cell. 153, 56-69 (2013).
141. Ecke I., et al. Antitumor effects of a combined 5-Aza-2'deoxycytidine and valproic acid treatment on rhabdomyosarcoma and medulloblastoma in Ptch mutant mice. Cancer Res. 69, 887-895 (2009).
142. Milde T., et al. HD-MB03 is a novel group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment. J. Neurooncol. 110, 335-348 (2012).
143. Spiller S.E., Ditzler S.H., Pullar B.J., & Olson J.M. Response of preclinical medulloblastoma models to combination therapy with 13-cis retinoic acid and suberoylanilide hydroxamic acid (SAHA). J. Neurooncol. 87, 133-141 (2008).
144. Hashizume R., et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat. Med. 20, 1394-1396 (2014).
145. Grasso C.S., et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med. 21, 827 (2015).
146. Alimova I., et al. Inhibition of EZH2 suppresses self-renewal and induces radiation sensitivity in atypical rhabdoid teratoid tumor cells. Neuro-oncol. 15, 149-160 (2013).
147. Kim E., et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell. 23, 839-852 (2013).
148. Filippakopoulos P., et al. Selective inhibition of BET bromodomains. Nature. 468, 1067-1073 (2010).
149. Henssen A., et al. BET bromodomain protein inhibition is a therapeutic option for medulloblastoma. Oncotarget. 4, 2080-2095 (2013).
150. Venkataraman S., et al. Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 5, 2355-2371 (2014).