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Nature medicine
Nov, 2017;23 (11): 1352-1361.

Targeting glioma stem cells through combined BMI1 and EZH2 inhibition.

Xun Jin, Leo J Y Kim, Qiulian Wu, Lisa C Wallace, Briana C Prager, Tanwarat Sanvoranart, Ryan C Gimple, Xiuxing Wang, Stephen C Mack, Tyler E Miller, Ping Huang, Claudia L Valentim, Qi-Gang Zhou, Jill S Barnholtz-Sloan, Shideng Bao, Andrew E Sloan, Jeremy N Rich
Author Information
  1. Xun Jin: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. ORCID
  2. Leo J Y Kim: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  3. Qiulian Wu: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  4. Lisa C Wallace: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  5. Briana C Prager: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  6. Tanwarat Sanvoranart: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  7. Ryan C Gimple: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  8. Xiuxing Wang: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  9. Stephen C Mack: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. ORCID
  10. Tyler E Miller: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  11. Ping Huang: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  12. Claudia L Valentim: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  13. Qi-Gang Zhou: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  14. Jill S Barnholtz-Sloan: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
  15. Shideng Bao: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  16. Andrew E Sloan: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
  17. Jeremy N Rich: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
PMID: 29035367 DOI: 10.1038/nm.4415

Abstract

Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.

References

  1. Oncogene. 2009 Apr 16;28(15):1807-11 [PMID: 19287454]
  2. Cancer Res. 2008 Nov 15;68(22):9125-30 [PMID: 19010882]
  3. J Neurosci. 2010 Jul 28;30(30):10096-111 [PMID: 20668194]
  4. Int J Clin Exp Pathol. 2014 Sep 15;7(10):6662-70 [PMID: 25400745]
  5. Nat Med. 2014 Jan;20(1):29-36 [PMID: 24292392]
  6. Nature. 1996 Jan 4;379(6560):88-91 [PMID: 8538748]
  7. Nat Med. 2017 Apr;23(4):483-492 [PMID: 28263309]
  8. J Neurosci. 2009 Jul 15;29(28):8884-96 [PMID: 19605626]
  9. Nature. 2012 Jan 29;482(7384):226-31 [PMID: 22286061]
  10. Cancer Lett. 2013 Jan 28;328(2):235-42 [PMID: 23022473]
  11. Nat Neurosci. 2013 Oct;16(10):1373-82 [PMID: 23995067]
  12. Nature. 2006 Dec 7;444(7120):756-60 [PMID: 17051156]
  13. Stem Cell Res. 2012 Mar;8(2):141-53 [PMID: 22265735]
  14. Neuro Oncol. 2011 Nov;13(11):1178-91 [PMID: 21940738]
  15. Genes Dev. 2013 May 1;27(9):985-90 [PMID: 23603901]
  16. Nat Med. 2017 Apr;23(4):493-500 [PMID: 28263307]
  17. Blood. 2006 Mar 1;107(5):2170-9 [PMID: 16293602]
  18. Cancer Cell. 2010 Jan 19;17(1):98-110 [PMID: 20129251]
  19. Cell Rep. 2013 Jan 31;3(1):260-73 [PMID: 23333277]
  20. Science. 2017 Mar 31;355(6332): [PMID: 28360267]
  21. Cancer Cell. 2009 Jun 2;15(6):501-13 [PMID: 19477429]
  22. Cancer Res. 2008 Aug 15;68(16):6507-15 [PMID: 18701473]
  23. Circulation. 2014 Jan 21;129(3):359-72 [PMID: 24163065]
  24. Nature. 2004 Oct 14;431(7010):873-8 [PMID: 15386022]
  25. Cancer Cell. 2017 Jul 10;32(1):42-56.e6 [PMID: 28697342]
  26. Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):E2646-55 [PMID: 24979766]
  27. Cancer Cell. 2010 Aug 9;18(2):185-97 [PMID: 20708159]
  28. Cell Stem Cell. 2009 May 8;4(5):440-52 [PMID: 19427293]
  29. J Med Chem. 2008 Feb 28;51(4):932-6 [PMID: 18217702]
  30. Cancer Cell. 2008 Jan;13(1):69-80 [PMID: 18167341]
  31. PLoS One. 2014 Aug 01;9(8):e103327 [PMID: 25084005]
  32. Cancer Cell. 2013 Jun 10;23(6):839-52 [PMID: 23684459]
  33. Cancer Res. 2011 Feb 1;71(3):779-89 [PMID: 21266355]
  34. Cancer Cell. 2007 Jan;11(1):69-82 [PMID: 17222791]
  35. Nature. 2004 Nov 18;432(7015):396-401 [PMID: 15549107]
  36. Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):851-6 [PMID: 25561528]
  37. Nat Genet. 2012 Jan 29;44(3):251-3 [PMID: 22286216]
  38. Cancer Res. 2009 Dec 15;69(24):9211-8 [PMID: 19934320]
  39. Science. 2014 Jun 20;344(6190):1396-401 [PMID: 24925914]
  40. Science. 2013 May 3;340(6132):626-30 [PMID: 23558169]
  41. Cancer Cell. 2013 Sep 9;24(3):331-46 [PMID: 23993863]
  42. Cell. 2013 Oct 10;155(2):462-77 [PMID: 24120142]
  43. Cancer Res. 2006 Aug 15;66(16):7843-8 [PMID: 16912155]
  44. Cancer Cell. 2015 Sep 14;28(3):307-317 [PMID: 26373278]
  45. J Neurol Sci. 2013 Dec 15;335(1-2):191-6 [PMID: 24139839]
  46. JCI Insight. 2017 May 18;2(10): [PMID: 28515364]
  47. Proc Natl Acad Sci U S A. 2013 May 21;110(21):8644-9 [PMID: 23650391]
  48. Nature. 2012 Feb 15;483(7390):479-83 [PMID: 22343889]
  49. Cell. 2012 Feb 17;148(4):664-78 [PMID: 22325148]
  50. Cell Rep. 2016 Dec 13;17(11):2994-3009 [PMID: 27974212]
  51. N Engl J Med. 2008 Jul 31;359(5):492-507 [PMID: 18669428]
  52. Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5248-53 [PMID: 24706837]
  53. Cell Death Differ. 2011 May;18(5):829-40 [PMID: 21127501]
  54. Nat Rev Cancer. 2007 Oct;7(10):733-6 [PMID: 17882276]
  55. Cancer Res. 2004 Oct 1;64(19):7011-21 [PMID: 15466194]
  56. Circ Res. 1997 Sep;81(3):297-303 [PMID: 9285630]
  57. Nat Rev Cancer. 2011 Apr;11(4):239-53 [PMID: 21430696]
  58. Int J Cancer. 2015 Oct 15;137(8):2007-18 [PMID: 25868794]
  59. Cancer Cell. 2007 Oct;12(4):328-41 [PMID: 17936558]
  60. Cancer Cell. 2013 May 13;23(5):660-76 [PMID: 23680149]

Grants

  1. R01 CA169117/NCI NIH HHS
  2. F30 CA217065/NCI NIH HHS
  3. R01 NS099175/NINDS NIH HHS
  4. F30 CA217066/NCI NIH HHS
  5. R01 NS087913/NINDS NIH HHS
  6. R01 NS103434/NINDS NIH HHS
  7. R35 CA197718/NCI NIH HHS
  8. F30 CA183510/NCI NIH HHS
  9. F30 CA203101/NCI NIH HHS
  10. R01 NS091080/NINDS NIH HHS
  11. R01 CA184090/NCI NIH HHS
  12. R01 CA171652/NCI NIH HHS
  13. R01 NS089272/NINDS NIH HHS
  14. T32 GM007250/NIGMS NIH HHS
  15. R01 CA154130/NCI NIH HHS

MeSH Term

Animals
Brain Neoplasms
Enhancer of Zeste Homolog 2 Protein
Epigenesis, Genetic
Glioblastoma
Humans
Mice
Neoplastic Stem Cells
Polycomb Repressive Complex 1
Reverse Transcriptase Polymerase Chain Reaction

Chemicals

BMI1 protein, human
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 1
Journal Article
Article has an altmetric score of 136

Word Cloud

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