Histone Modifying Enzymes and Chromatin Modifiers in Glioma Pathobiology and Therapy Responses

  • Iwona A. Ciechomska
  • Chinchu Jayaprakash
  • Marta Maleszewska
  • Bozena KaminskaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1202)


Signal transduction pathways directly communicate and transform chromatin to change the epigenetic landscape and regulate gene expression. Chromatin acts as a dynamic platform of signal integration and storage. Histone modifications and alteration of chromatin structure play the main role in chromatin-based gene expression regulation. Alterations in genes coding for histone modifying enzymes and chromatin modifiers result in malfunction of proteins that regulate chromatin modification and remodeling. Such dysregulations culminate in profound changes in chromatin structure and distorted patterns of gene expression. Gliomagenesis is a multistep process, involving both genetic and epigenetic alterations. Recent applications of next generation sequencing have revealed that many chromatin regulation-related genes, including ATRX, ARID1A, SMARCA4, SMARCA2, SMARCC2, BAF155 and hSNF5 are mutated in gliomas. In this review we summarize newly identified mechanisms affecting expression or functions of selected histone modifying enzymes and chromatin modifiers in gliomas. We focus on selected examples of pathogenic mechanisms involving ATRX, histone methyltransferase G9a, histone acetylases/deacetylases and chromatin remodeling complexes SMARCA2/4. We discuss the impact of selected epigenetics alterations on glioma pathobiology, signaling and therapeutic responses. We assess the attempts of targeting defective pathways with new inhibitors.


Histone modifications Transcription regulation Glioma, histone modifying enzyme inhibitors Epi-drugs 



Active DNA-dependent ATPase A domain inhibitor


AT-rich interactive domain-containing protein 1A


Autophagy related gene


Thalassaemia/mental retardation syndrome X-linked


Bromodomain and extraterminal domain




Death-domain associated protein


DNA methyltransferase-1


Double-strand break


Euchromatic histone-lysine N-methyltransferase 2


Enhancer of zeste homolog 2




G9a-like protein


Glioma stem cell


Histone acetyltransferase


Histone deacetylase


Histone methyltransferase

MBT domain

Malignant brain tumor domain


p300/CBP Associated factor

PcG protein

Polycomb Group protein


Replication protein A 70




SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2


SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4


Suppressor of variegation 3–9 homologue 1


SWItch/sucrose non-fermentable


The cancer genome atlas





Supported by a grant from the Polish National Science Centre [DEC-2015/16/W/NZ2/00314].


  1. Ahmad F, Dixit D, Joshi SD et al (2016) G9a inhibition induced PKM2 regulates autophagic responses. Int J Biochem Cell Biol 78:87–95. CrossRefPubMedGoogle Scholar
  2. Amankwah EK, Thompson RC, Nabors LB et al (2013) SWI/SNF gene variants and glioma risk and outcome. Cancer Epidemiol 37:162–165. CrossRefPubMedGoogle Scholar
  3. Bai J, Mei P-J, Liu H et al (2012) BRG1 expression is increased in human glioma and controls glioma cell proliferation, migration and invasion in vitro. J Cancer Res Clin Oncol 138:991–998. CrossRefPubMedGoogle Scholar
  4. Bai J, Mei P, Zhang C et al (2013) BRG1 is a prognostic marker and potential therapeutic target in human breast cancer. PLoS One 8:e59772. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21:381–395. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Biankin AV, Waddell N, Kassahn KS et al (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491:399–405. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bitler BG, Aird KM, Garipov A et al (2015) Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med 21:231–238. CrossRefPubMedGoogle Scholar
  8. Bowers EM, Yan G, Mukherjee C et al (2010) Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem Biol 17:471–482. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cai J, Chen J, Zhang W et al (2015) Loss of ATRX, associated with DNA methylation pattern of chromosome end, impacted biological behaviors of astrocytic tumors. Oncotarget 6:18105–18115. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Cancer Genome Atlas Research Network TCGA et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481–2498. CrossRefGoogle Scholar
  11. Casciello F, Windloch K, Gannon F et al (2015) Functional role of G9a histone methyltransferase in cancer. Front Immunol 6:487. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Chang Y, Zhang X, Horton JR et al (2009) Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat Struct Mol Biol 16:312–317. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Chang Y, Ganesh T, Horton JR et al (2010) Adding a lysine mimic in the design of potent inhibitors of histone lysine methyltransferases. J Mol Biol 400:1–7. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Chen M-W, Hua K-T, Kao H-J et al (2010) H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res 70:7830–7840. CrossRefPubMedGoogle Scholar
  15. Chen W-L, Sun H-P, Li D-D et al (2017) G9a – an appealing antineoplastic target. Curr Cancer Drug Targets 17:555–568. CrossRefPubMedGoogle Scholar
  16. Cherblanc FL, Chapman KL, Brown R et al (2013) Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases. Nat Chem Biol 9:136–137. CrossRefPubMedGoogle Scholar
  17. Chin HG, Estève P-O, Pradhan M et al (2007) Automethylation of G9a and its implication in wider substrate specificity and HP1 binding. Nucleic Acids Res 35:7313–7323. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Choudhary C, Kumar C, Gnad F et al (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840. CrossRefPubMedGoogle Scholar
  19. Chung C, Coste H, White JH et al (2011) Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J Med Chem 54:3827–3838. CrossRefPubMedGoogle Scholar
  20. Ciechomska IA, Przanowski P, Jackl J et al (2016) BIX01294, an inhibitor of histone methyltransferase, induces autophagy-dependent differentiation of glioma stem-like cells. Sci Rep 6:38723. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Ciechomska IA, Marciniak MP, Jackl J et al (2018) Pre-treatment or post-treatment of human glioma cells with BIX01294, the inhibitor of histone methyltransferase G9a, sensitizes cells to temozolomide. Front Pharmacol 9:1271. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Côté J, Peterson CL, Workman JL (1998) Perturbation of nucleosome core structure by the SWI/SNF complex persists after its detachment, enhancing subsequent transcription factor binding. Proc Natl Acad Sci U S A 95:4947–4952. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Culmes M, Eckstein H-H, Burgkart R et al (2013) Endothelial differentiation of adipose-derived mesenchymal stem cells is improved by epigenetic modifying drug BIX-01294. Eur J Cell Biol 92:70–79. CrossRefPubMedGoogle Scholar
  24. Curry E, Green I, Chapman-Rothe N et al (2015) Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells. Clin Epigenetics 7:84. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Danussi C, Bose P, Parthasarathy PT et al (2018) Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling. Nat Commun 9:1057. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Dutta P, Tanti GK, Sharma S et al (2012) Global epigenetic changes induced by SWI2/SNF2 inhibitors characterize neomycin-resistant mammalian cells. PLoS One 7:e49822. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Dykhuizen EC, Hargreaves DC, Miller EL et al (2013) BAF complexes facilitate decatenation of DNA by topoisomerase IIα. Nature 497:624–627. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Eckschlager T, Plch J, Stiborova M et al (2017) Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci 18:1414. CrossRefPubMedCentralGoogle Scholar
  29. Eguía-Aguilar P, Solís-Paredes M, Reyes-Cid P et al (2013) Expression of histone acetylases p300 and PCAF in pediatric astrocytomas. Childs Nerv Syst 29:1089–1096. CrossRefPubMedGoogle Scholar
  30. Estève P-O, Chin HG, Smallwood A et al (2006) Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev 20:3089–3103. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Euskirchen G, Auerbach RK, Snyder M (2012) SWI/SNF chromatin-remodeling factors: multiscale analyses and diverse functions. J Biol Chem 287:30897–30905. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Fedorov O, Castex J, Tallant C et al (2015) Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance. Sci Adv 1:e1500723. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Ferguson SD, Xiu J, Weathers S-P et al (2016) GBM-associated mutations and altered protein expression are more common in young patients. Oncotarget 7:69466–69478. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Ferri E, Petosa C, McKenna CE (2016) Bromodomains: structure, function and pharmacology of inhibition. Biochem Pharmacol 106:1–18. CrossRefPubMedGoogle Scholar
  35. Filippakopoulos P, Qi J, Picaud S et al (2010) Selective inhibition of BET bromodomains. Nature 468:1067–1073. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Fujimoto A, Totoki Y, Abe T et al (2012) Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 44:760–764. CrossRefPubMedGoogle Scholar
  37. Fujishiro S, Dodo K, Iwasa E et al (2013) Epidithiodiketopiperazine as a pharmacophore for protein lysine methyltransferase G9a inhibitors: reducing cytotoxicity by structural simplification. Bioorg Med Chem Lett 23:733–736. CrossRefPubMedGoogle Scholar
  38. Ghildiyal R, Sen E (2017) Concerted action of histone methyltransferases G9a and PRMT-1 regulates PGC-1α-RIG-I axis in IFNγ treated glioma cells. Cytokine 89:185–193. CrossRefPubMedGoogle Scholar
  39. Glaros S, Cirrincione GM, Muchardt C et al (2007) The reversible epigenetic silencing of BRM: implications for clinical targeted therapy. Oncogene 26:7058–7066. CrossRefPubMedGoogle Scholar
  40. Gramling S, Rogers C, Liu G et al (2011) Pharmacologic reversal of epigenetic silencing of the anticancer protein BRM: a novel targeted treatment strategy. Oncogene 30:3289–3294. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Guo A-S, Huang Y-Q, Ma X-D et al (2016) Mechanism of G9a inhibitor BIX-01294 acting on U251 glioma cells. Mol Med Rep 14:4613–4621. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Gursoy-Yuzugullu O, Carman C, Serafim RB et al (2017) Epigenetic therapy with inhibitors of histone methylation suppresses DNA damage signaling and increases glioma cell radiosensitivity. Oncotarget 8:24518–24532. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Hargreaves DC, Crabtree GR (2011) ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res 21:396–420. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Harte MT, O’Brien GJ, Ryan NM et al (2010) BRD7, a subunit of SWI/SNF complexes, binds directly to BRCA1 and regulates BRCA1-dependent transcription. Cancer Res 70:2538–2547. CrossRefGoogle Scholar
  45. Helming KC, Wang X, Roberts CWM (2014) Vulnerabilities of mutant SWI/SNF complexes in cancer. Cancer Cell 26:309–317. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Herait PE, Berthon C, Thieblemont C et al (2014) BET-bromodomain inhibitor OTX015 shows clinically meaningful activity at nontoxic doses: interim results of an ongoing phase I trial in hematologic malignancies. Clin Trials Am Assoc Cancer Res 74:CT231. CrossRefGoogle Scholar
  47. Hoffman GR, Rahal R, Buxton F et al (2014) Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc Natl Acad Sci U S A 111:3128–3133. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Hohmann AF, Vakoc CR (2014) A rationale to target the SWI/SNF complex for cancer therapy. Trends Genet 30:356–363. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Huang J, Dorsey J, Chuikov S, Zhang X, Jenuwein T, Reinberg D, Berger SL (2010) G9a and Glp methylate lysine 373 in the tumor suppressor p53. J Biol Chem 285:9636–9641. CrossRefGoogle Scholar
  50. Hu Z, Zhou J, Jiang J et al (2019) Genomic characterization of genes encoding histone acetylation modulator proteins identifies therapeutic targets for cancer treatment. Nat Commun 10:733. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Iwasa E, Hamashima Y, Fujishiro S et al (2010) Total synthesis of (+)-chaetocin and its analogues: their histone methyltransferase G9a inhibitory activity. J Am Chem Soc 132:4078–4079. CrossRefPubMedGoogle Scholar
  52. Johnson BE, Mazor T, Hong C et al (2014) Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343:189–193. CrossRefPubMedGoogle Scholar
  53. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128:683–692. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Kadam S, Emerson BM (2003) Transcriptional specificity of human SWI/SNF BRG1 and BRM chromatin remodeling complexes. Mol Cell 11:377–389. CrossRefPubMedGoogle Scholar
  55. Kadoch C, Hargreaves DC, Hodges C et al (2013) Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet 45:592–601. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Kahali B, Gramling SJB, Marquez SB et al (2014a) Identifying targets for the restoration and reactivation of BRM. Oncogene 33:653–664. CrossRefPubMedGoogle Scholar
  57. Kahali B, Yu J, Marquez SB et al (2014b) The silencing of the SWI/SNF subunit and anticancer gene BRM in Rhabdoid tumors. Oncotarget 5:3316–3332. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Kapoor P, Bao Y, Xiao J et al (2015) Regulation of Mec1 kinase activity by the SWI/SNF chromatin remodeling complex. Genes Dev 29:591–602. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Kim Y, Kim Y-S, Kim DE et al (2013) BIX-01294 induces autophagy-associated cell death via EHMT2/G9a dysfunction and intracellular reactive oxygen species production. Autophagy 9:2126–2139. CrossRefPubMedGoogle Scholar
  60. Kim MY, Park S-J, Shim JW et al (2017) Accumulation of low-dose BIX01294 promotes metastatic potential of U251 glioblastoma cells. Oncol Lett 13:1767–1774. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8:931–937. CrossRefPubMedGoogle Scholar
  62. Kondengaden SM, Luo L, Huang K et al (2016) Discovery of novel small molecule inhibitors of lysine methyltransferase G9a and their mechanism in leukemia cell lines. Eur J Med Chem 122:382–393. CrossRefPubMedGoogle Scholar
  63. Kondo Y, Shen L, Suzuki S et al (2007) Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas. Hepatol Res 37:974–983. CrossRefPubMedGoogle Scholar
  64. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705. CrossRefPubMedGoogle Scholar
  65. Kramer JM (2016) Regulation of cell differentiation and function by the euchromatin histone methyltranserfases G9a and GLP. Biochem Cell Biol 94:26–32. CrossRefPubMedGoogle Scholar
  66. Kubicek S, O’Sullivan RJ, August EM et al (2007) Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell 25:473–481. CrossRefPubMedGoogle Scholar
  67. Lathia JD, Mack SC, Mulkearns-Hubert EE et al (2015) Cancer stem cells in glioblastoma. Genes Dev 29:1203–1217. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Lehnertz B, Northrop JP, Antignano F et al (2010) Activating and inhibitory functions for the histone lysine methyltransferase G9a in T helper cell differentiation and function. J Exp Med 207:915–922. CrossRefPubMedPubMedCentralGoogle Scholar
  69. Lehnertz B, Pabst C, Su L et al (2014) The methyltransferase G9a regulates HoxA9-dependent transcription in AML. Genes Dev 28:317–327. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Leung DC, Dong KB, Maksakova IA et al (2011) Lysine methyltransferase G9a is required for de novo DNA methylation and the establishment, but not the maintenance, of proviral silencing. Proc Natl Acad Sci U S A 108:5718–5723. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Li Y, Shi Q, Jin X et al (2006) BRG1 expression in prostate carcinoma by application of tissue microarray. Zhonghua Nan Ke Xue 12:629–632PubMedGoogle Scholar
  72. Ling BMT, Gopinadhan S, Kok WK et al (2012) G9a mediates Sharp-1-dependent inhibition of skeletal muscle differentiation. Mol Biol Cell 23:4778. CrossRefGoogle Scholar
  73. Liu F, Barsyte-Lovejoy D, Allali-Hassani A et al (2011) Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy-quinazolines. J Med Chem 54:6139–6150. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Liu X-Y, Gerges N, Korshunov A et al (2012) Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol 124:615–625. CrossRefPubMedGoogle Scholar
  75. Liu F, Barsyte-Lovejoy D, Li F et al (2013) Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J Med Chem 56:8931–8942. CrossRefPubMedGoogle Scholar
  76. Lucio-Eterovic AK, Cortez MA, Valera ET et al (2008) Differential expression of 12 histone deacetylase (HDAC) genes in astrocytomas and normal brain tissue: class II and IV are hypoexpressed in glioblastomas. BMC Cancer 8:243. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Lulla RR, Saratsis AM, Hashizume R (2016) Mutations in chromatin machinery and pediatric high-grade glioma. Sci Adv 2:e1501354. CrossRefPubMedPubMedCentralGoogle Scholar
  78. Malatesta M, Steinhauer C, Mohammad F et al (2013) Histone acetyltransferase PCAF is required for Hedgehog-Gli-dependent transcription and cancer cell proliferation. Cancer Res 73:6323–6333. CrossRefPubMedGoogle Scholar
  79. Maleszewska M, Kaminska B (2015) Deregulation of histone-modifying enzymes and chromatin structure modifiers contributes to glioma development. Future Oncol 11:2587–2601. CrossRefPubMedGoogle Scholar
  80. Maleszewska M, Steranka A, Kaminska B (2014) The effects of selected inhibitors of histone modifying enzyme on C6 glioma cells. Pharmacol Rep 66:107–113. CrossRefPubMedGoogle Scholar
  81. Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6:838–849. CrossRefPubMedGoogle Scholar
  82. Masliah-Planchon J, Bièche I, Guinebretière J-M et al (2015) SWI/SNF chromatin remodeling and human malignancies. Annu Rev Pathol Mech Dis 10:145–171. CrossRefGoogle Scholar
  83. Maze I, Covington HE, Dietz DM et al (2010) Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 327:213–216. CrossRefPubMedPubMedCentralGoogle Scholar
  84. Mezentseva NV, Yang J, Kaur K et al (2013) The histone methyltransferase inhibitor BIX01294 enhances the cardiac potential of bone marrow cells. Stem Cells Dev 22:654–667. CrossRefPubMedGoogle Scholar
  85. Miller RE, Brough R, Bajrami I et al (2016) Synthetic lethal targeting of ARID1A-mutant ovarian clear cell tumors with dasatinib. Mol Cancer Ther 15:1472–1484. CrossRefPubMedGoogle Scholar
  86. Mirguet O, Gosmini R, Toum J et al (2013) Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J Med Chem 56:7501–7515. CrossRefPubMedGoogle Scholar
  87. Mozzetta C, Pontis J, Fritsch L et al (2014) The histone H3 lysine 9 methyltransferases G9a and GLP regulate polycomb repressive complex 2-mediated gene silencing. Mol Cell 53:277–289. CrossRefPubMedGoogle Scholar
  88. Muthuswami R, Mesner LD, Wang D et al (2000) Phosphoaminoglycosides inhibit SWI2/SNF2 family DNA-dependent molecular motor domains. Biochemistry 39:4358–4365. CrossRefPubMedGoogle Scholar
  89. Narvajas AA-M, Gomez TS, Zhang J-S et al (2013) Epigenetic regulation of autophagy by the methyltransferase G9a. Mol Cell Biol 33:3983. CrossRefGoogle Scholar
  90. Nicodeme E, Jeffrey KL, Schaefer U et al (2010) Suppression of inflammation by a synthetic histone mimic. Nature 468:1119–1123. CrossRefPubMedPubMedCentralGoogle Scholar
  91. Nijman SMB (2011) Synthetic lethality: general principles, utility and detection using genetic screens in human cells. FEBS Lett 585:1–6. CrossRefPubMedPubMedCentralGoogle Scholar
  92. Nikoletopoulou V, Markaki M, Palikaras K et al (2013) Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta, Mol Cell Res 1833:3448–3459. CrossRefPubMedGoogle Scholar
  93. Oike T, Ogiwara H, Tominaga Y et al (2013) A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res 73:5508–5518. CrossRefPubMedGoogle Scholar
  94. Pappano WN, Guo J, He Y et al (2015) The histone methyltransferase inhibitor A-366 uncovers a role for G9a/GLP in the epigenetics of leukemia. PLoS One 10:e0131716. CrossRefPubMedPubMedCentralGoogle Scholar
  95. Porkholm M, Raunio A, Vainionpää R et al (2018) Molecular alterations in pediatric brainstem gliomas. Pediatr Blood Cancer 65:e26751. CrossRefGoogle Scholar
  96. Romero FA, Taylor AM, Crawford TD et al (2016) Disrupting acetyl-lysine recognition: progress in the development of bromodomain inhibitors. J Med Chem 59:1271–1298. CrossRefPubMedGoogle Scholar
  97. San José-Enériz E, Agirre X, Rabal O et al (2017) Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies. Nat Commun 8:15424. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Schaefer A, Sampath SC, Intrator A et al (2009) Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron 64:678–691. CrossRefPubMedPubMedCentralGoogle Scholar
  99. Schwartzentruber J, Korshunov A, Liu X-Y et al (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231. CrossRefPubMedGoogle Scholar
  100. Shain AH, Pollack JR (2013) The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS One 8:e55119. CrossRefPubMedPubMedCentralGoogle Scholar
  101. Sharma S, Gerke DS, Han HF et al (2012) Lysine methyltransferase G9a is not required for DNMT3A/3B anchoring to methylated nucleosomes and maintenance of DNA methylation in somatic cells. Epigenetics Chromatin 5:3. CrossRefPubMedPubMedCentralGoogle Scholar
  102. Shorstova T, Marques M, Su J et al (2019) SWI/SNF-compromised cancers are susceptible to bromodomain inhibitors. Cancer Res 79:2761–2774. CrossRefPubMedGoogle Scholar
  103. Son EY, Crabtree GR (2014) The role of BAF (mSWI/SNF) complexes in mammalian neural development. Am J Med Genet C Semin Med Genet 166C:333–349. CrossRefPubMedGoogle Scholar
  104. St. Pierre R, Kadoch C (2017) Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. Curr Opin Genet Dev 42:56–67. CrossRefPubMedPubMedCentralGoogle Scholar
  105. Sun A, Tawfik O, Gayed B et al (2007) Aberrant expression of SWI/SNF catalytic subunits BRG1/BRM is associated with tumor development and increased invasiveness in prostate cancers. Prostate 67:203–213. CrossRefPubMedGoogle Scholar
  106. Sundaresan NR, Pillai VB, Wolfgeher D et al (2011) The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci Signal 4:ra46. CrossRefPubMedGoogle Scholar
  107. Sweis RF, Pliushchev M, Brown PJ et al (2014) Discovery and development of potent and selective inhibitors of histone methyltransferase G9a. ACS Med Chem Lett 5:205–209. CrossRefPubMedPubMedCentralGoogle Scholar
  108. Tachibana M, Sugimoto K, Fukushima T et al (2001) SET domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to Lysines 9 and 27 of histone H3. J Biol Chem 276:25309–25317. CrossRefPubMedGoogle Scholar
  109. Tachibana M, Sugimoto K, Nozaki M et al (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16:1779–1791. CrossRefPubMedPubMedCentralGoogle Scholar
  110. Tachibana M, Ueda J, Fukuda M et al (2005) Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev 19:815–826. CrossRefPubMedPubMedCentralGoogle Scholar
  111. Tachibana M, Nozaki M, Takeda N et al (2007) Functional dynamics of H3K9 methylation during meiotic prophase progression. EMBO J 26:3346–3359. CrossRefPubMedPubMedCentralGoogle Scholar
  112. Tachibana M, Matsumura Y, Fukuda M et al (2008) G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. EMBO J 27:2681–2690. CrossRefPubMedPubMedCentralGoogle Scholar
  113. Tan M, Luo H, Lee S et al (2011) Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146:1016–1028. CrossRefPubMedPubMedCentralGoogle Scholar
  114. Tao H, Li H, Su Y et al (2014) Histone methyltransferase G9a and H3K9 dimethylation inhibit the self-renewal of glioma cancer stem cells. Mol Cell Biochem 394:23–30. CrossRefPubMedGoogle Scholar
  115. Theodoulou NH, Tomkinson NC, Prinjha RK et al (2016) Clinical progress and pharmacology of small molecule bromodomain inhibitors. Curr Opin Chem Biol 33:58–66. CrossRefPubMedGoogle Scholar
  116. Thomas LR, Miyashita H, Cobb RM, Pierce S et al (2008) Functional analysis of histone methyltransferase g9a in B and T lymphocytes. J Immunol 181:485–493. CrossRefPubMedPubMedCentralGoogle Scholar
  117. Trojer P, Zhang J, Yonezawa M et al (2009) Dynamic histone H1 isotype 4 methylation and demethylation by histone lysine methyltransferase G9a/KMT1C and the jumonji domain-containing JMJD2/KDM4 proteins. J Biol Chem 284:8395–8405. CrossRefPubMedPubMedCentralGoogle Scholar
  118. Turner BM (2012) The adjustable nucleosome: an epigenetic signaling module. Trends Genet 28:436–444. CrossRefPubMedGoogle Scholar
  119. Vangamudi B, Paul TA, Shah PK et al (2015) The SMARCA2/4 ATPase domain surpasses the bromodomain as a drug target in SWI/SNF-mutant cancers: insights from cDNA rescue and PFI-3 inhibitor studies. Cancer Res 75:3865–3878. CrossRefPubMedPubMedCentralGoogle Scholar
  120. Vedadi M, Barsyte-Lovejoy D, Liu F et al (2011) A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol 7:566–574. CrossRefPubMedPubMedCentralGoogle Scholar
  121. Wang Y, Yang J, Wild AT et al (2019) G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma. Nat Commun 10:943. CrossRefPubMedPubMedCentralGoogle Scholar
  122. Was H, Krol SK, Rotili D et al (2019) Histone deacetylase inhibitors exert anti-tumor effects on human adherent and stem-like glioma cells. Clin Epigenetics 11:11. CrossRefPubMedPubMedCentralGoogle Scholar
  123. Watanabe H, Soejima K, Yasuda H et al (2008) Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells. Cancer Cell Int 8:15. CrossRefPubMedPubMedCentralGoogle Scholar
  124. Watanabe T, Semba S, Yokozaki H (2011) Regulation of PTEN expression by the SWI/SNF chromatin-remodelling protein BRG1 in human colorectal carcinoma cells. Br J Cancer 104:146–154. CrossRefPubMedGoogle Scholar
  125. Williams EA, Miller JJ, Tummala SS et al (2018) TERT promoter wild-type glioblastomas show distinct clinical features and frequent PI3K pathway mutations. Acta Neuropathol Commun 6:106. CrossRefPubMedPubMedCentralGoogle Scholar
  126. Wilson BG, Wang X, Shen X et al (2010) Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18:316–328. CrossRefPubMedPubMedCentralGoogle Scholar
  127. Wilson BG, Helming KC, Wang X et al (2014) Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Mol Cell Biol 34:1136–1144. CrossRefPubMedPubMedCentralGoogle Scholar
  128. Wong AK, Shanahan F, Chen Y et al (2000) BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines. Cancer Res 60:6171–6177PubMedGoogle Scholar
  129. Wozniak RJ, Klimecki WT, Lau SS et al (2007) 5-Aza-2′-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation. Oncogene 26:77–90. CrossRefPubMedGoogle Scholar
  130. Wu H, Chen X, Xiong J et al (2011) Histone methyltransferase G9a contributes to H3K27 methylation in vivo. Cell Res 21:365–367. CrossRefPubMedGoogle Scholar
  131. Wu Q, Sharma S, Cui H et al (2016) Targeting the chromatin remodeling enzyme BRG1 increases the efficacy of chemotherapy drugs in breast cancer cells. Oncotarget 7:27158–27175. CrossRefPubMedPubMedCentralGoogle Scholar
  132. Xiong Y, Li F, Babault N et al (2017) Discovery of potent and selective inhibitors for G9a-like protein (GLP) lysine methyltransferase. J Med Chem 60:1876–1891. CrossRefPubMedPubMedCentralGoogle Scholar
  133. Xu L-X, Li Z-H, Tao Y-F et al (2014) Histone acetyltransferase inhibitor II induces apoptosis in glioma cell lines via the p53 signaling pathway. J Exp Clin Cancer Res 33:108. CrossRefPubMedPubMedCentralGoogle Scholar
  134. Yamamichi N, Yamamichi-Nishina M, Mizutani T et al (2005) The Brm gene suppressed at the post-transcriptional level in various human cell lines is inducible by transient HDAC inhibitor treatment, which exhibits antioncogenic potential. Oncogene 24:5471–5481. CrossRefPubMedGoogle Scholar
  135. Yang Q, Lu Z, Singh D et al (2012) BIX-01294 treatment blocks cell proliferation, migration and contractility in ovine foetal pulmonary arterial smooth muscle cells. Cell Prolif 45:335–344. CrossRefPubMedPubMedCentralGoogle Scholar
  136. Yang J, Kaur K, Ong LL et al (2015) Inhibition of G9a histone methyltransferase converts bone marrow mesenchymal stem cells to cardiac competent progenitors. Stem Cells Int 2015:270428. CrossRefPubMedPubMedCentralGoogle Scholar
  137. Yang Q, Zhu Q, Lu X et al (2017) G9a coordinates with the RPA complex to promote DNA damage repair and cell survival. Proc Natl Acad Sci U S A 114:E6054–E6063. CrossRefPubMedPubMedCentralGoogle Scholar
  138. Yu Y, Song C, Zhang Q et al (2012) Histone H3 lysine 56 methylation regulates DNA replication through its interaction with PCNA. Mol Cell 46:7. CrossRefPubMedPubMedCentralGoogle Scholar
  139. Yuan Y, Wang Q, Paulk J et al (2012) A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. ACS Chem Biol 7:1152–1157. CrossRefPubMedPubMedCentralGoogle Scholar
  140. Yun M, Wu J, Workman JL et al (2011) Readers of histone modifications. Cell Res 21:564–578. CrossRefPubMedPubMedCentralGoogle Scholar
  141. Zeng L, Zhang Q, Li S, Plotnikov AN, Walsh MJ, Zhou MM (2010) Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b. Nature 466:258–262. CrossRefGoogle Scholar
  142. Zang L, Kondengaden SM, Zhang Q et al (2017) Structure based design, synthesis and activity studies of small hybrid molecules as HDAC and G9a dual inhibitors. Oncotarget 8:63187–63207. CrossRefPubMedPubMedCentralGoogle Scholar
  143. Zhang K, Wang J, Yang L et al (2018) Targeting histone methyltransferase G9a inhibits growth and Wnt signaling pathway by epigenetically regulating HP1α and APC2 gene expression in non-small cell lung cancer. Mol Cancer 17:153. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Iwona A. Ciechomska
    • 1
  • Chinchu Jayaprakash
    • 1
  • Marta Maleszewska
    • 1
  • Bozena Kaminska
    • 1
    Email author
  1. 1.Laboratory of Molecular Neurobiology, Neurobiology CenterNencki Institute of Experimental BiologyWarsawPoland

Personalised recommendations