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D'Oto A, Fang J, Jin H, et al. KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma. Nat Commun. 2021;12(1):7204doi: 10.1038/s41467-021-27502-2.
D'Oto, A., Fang, J., Jin, H., Xu, B., Singh, S., Mullasseril, A., Jones, V., Abu-Zaid, A., von Buttlar, X., Cooke, B., Hu, D., Shohet, J., Murphy, A. J., Davidoff, A. M., & Yang, J. (2021). KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma. Nature communications, 12(1), 7204. https://doi.org/10.1038/s41467-021-27502-2
D'Oto, Alexandra, et al. "KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma." Nature communications vol. 12,1 (2021): 7204. doi: https://doi.org/10.1038/s41467-021-27502-2
D'Oto A, Fang J, Jin H, Xu B, Singh S, Mullasseril A, Jones V, Abu-Zaid A, von Buttlar X, Cooke B, Hu D, Shohet J, Murphy AJ, Davidoff AM, Yang J. KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma. Nat Commun. 2021 Dec 10;12(1):7204. doi: 10.1038/s41467-021-27502-2. PMID: 34893606; PMCID: PMC8664842.
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Nat Commun. 2021 Dec 10;12(1):7204. doi: 10.1038/s41467-021-27502-2.

KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma.

Nature communications

Alexandra D'Oto, Jie Fang, Hongjian Jin, Beisi Xu, Shivendra Singh, Anoushka Mullasseril, Victoria Jones, Ahmed Abu-Zaid, Xinyu von Buttlar, Bailey Cooke, Dongli Hu, Jason Shohet, Andrew J Murphy, Andrew M Davidoff, Jun Yang

Affiliations

  1. Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  2. Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  3. Department of Pediatrics, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA.
  4. Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. [email protected].
  5. Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. [email protected].

PMID: 34893606 PMCID: PMC8664842 DOI: 10.1038/s41467-021-27502-2

Abstract

The H3K27me2/me3 histone demethylase KDM6B is essential to neuroblastoma cell survival. However, the mechanism of KDM6B action remains poorly defined. We demonstrate that inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and the KDM6 inhibitor GSK-J4. These data indicate that KDM6B promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.

© 2021. The Author(s).

References

  1. Cell. 2009 Jun 26;137(7):1194-211 - PubMed
  2. Nat Protoc. 2020 Oct;15(10):3264-3283 - PubMed
  3. Curr Protoc Mol Biol. 2015 Jan 05;109:21.29.1-21.29.9 - PubMed
  4. Nat Genet. 2018 Apr;50(4):515-523 - PubMed
  5. Nat Biotechnol. 2011 Jan;29(1):24-6 - PubMed
  6. Cancer Cell. 2018 Jul 9;34(1):9-20 - PubMed
  7. Cancer Res. 1998 Jun 15;58(12):2624-32 - PubMed
  8. Bioinformatics. 2009 Jul 15;25(14):1754-60 - PubMed
  9. Nature. 2007 Oct 11;449(7163):731-4 - PubMed
  10. Nat Commun. 2014 Apr 08;5:3630 - PubMed
  11. Cell Growth Differ. 1995 Mar;6(3):229-37 - PubMed
  12. Clin Cancer Res. 2013 Nov 15;19(22):6173-82 - PubMed
  13. J Natl Cancer Inst. 2015 Apr 29;107(6):djv080 - PubMed
  14. Nat Chem Biol. 2016 Jul;12(7):539-45 - PubMed
  15. J Biol Chem. 2003 Jan 31;278(5):2983-9 - PubMed
  16. Elife. 2017 Jan 16;6: - PubMed
  17. Genes Chromosomes Cancer. 2012 Jan;51(1):10-9 - PubMed
  18. Oncotarget. 2017 Jul 8;8(37):62131-62142 - PubMed
  19. Cell Res. 2018 Feb;28(2):204-220 - PubMed
  20. Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5 - PubMed
  21. Genes Chromosomes Cancer. 2007 Oct;46(10):936-49 - PubMed
  22. Cancer Cell. 2002 Aug;2(2):103-12 - PubMed
  23. Cancer Discov. 2013 Mar;3(3):308-23 - PubMed
  24. Cancer Discov. 2016 Apr;6(4):353-67 - PubMed
  25. Cancer Res. 2014 Mar 15;74(6):1705-17 - PubMed
  26. Cancer Res. 2017 Sep 1;77(17):4626-4638 - PubMed
  27. Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):2544-9 - PubMed
  28. Cell. 2014 Dec 18;159(7):1665-80 - PubMed
  29. PLoS One. 2017 Apr 6;12(4):e0174775 - PubMed
  30. Nucleic Acids Res. 2006 Jan 1;34(Database issue):D108-10 - PubMed
  31. Oncogene. 2007 Nov 22;26(53):7432-44 - PubMed
  32. Nature. 2010 Sep 23;467(7314):430-5 - PubMed
  33. Nature. 2014 Oct 23;514(7523):513-7 - PubMed
  34. Science. 2007 Oct 19;318(5849):447-50 - PubMed
  35. Nature. 2017 Mar 23;543(7646):519-524 - PubMed
  36. Nat Genet. 2015 Jan;47(1):8-12 - PubMed
  37. Nat Chem Biol. 2016 Feb;12(2):109-16 - PubMed
  38. Nature. 2014 Oct 2;514(7520):E1-2 - PubMed
  39. Oncogenesis. 2019 Jan 4;8(1):3 - PubMed
  40. Genes Dev. 2016 Jul 1;30(13):1492-502 - PubMed
  41. Oncogene. 2010 Mar 4;29(9):1249-59 - PubMed
  42. Nature. 2012 Aug 16;488(7411):404-8 - PubMed
  43. Cell. 2013 Nov 7;155(4):934-47 - PubMed
  44. Cell Res. 2011 Mar;21(3):381-95 - PubMed
  45. Cell. 2007 Sep 21;130(6):1083-94 - PubMed
  46. Nucleic Acids Res. 2018 Apr 20;46(7):3351-3365 - PubMed
  47. Methods Mol Biol. 2016;1342:71-88 - PubMed
  48. Cell. 2014 Nov 20;159(5):1126-1139 - PubMed
  49. Oncogene. 2005 Feb 24;24(9):1533-41 - PubMed
  50. Genes Chromosomes Cancer. 2005 Aug;43(4):390-403 - PubMed
  51. Leukemia. 2017 Dec;31(12):2661-2669 - PubMed
  52. Nat Rev Cancer. 2013 Jun;13(6):397-411 - PubMed
  53. Genes Dev. 2009 May 15;23(10):1177-82 - PubMed
  54. Clin Cancer Res. 2015 Dec 1;21(23):5391-403 - PubMed
  55. Cell. 2013 Apr 11;153(2):307-19 - PubMed
  56. Nature. 2012 Feb 22;483(7391):589-93 - PubMed
  57. Cell Syst. 2018 Jan 24;6(1):13-24 - PubMed
  58. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18439-44 - PubMed
  59. Nat Methods. 2013 Dec;10(12):1213-8 - PubMed
  60. Sci Transl Med. 2018 May 16;10(441): - PubMed
  61. Nat Rev Cancer. 2018 Jul;18(7):442-451 - PubMed
  62. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 - PubMed
  63. Nature. 2010 Dec 23;468(7327):1067-73 - PubMed
  64. Genome Biol. 2008;9(9):R137 - PubMed
  65. Oncogene. 2018 May;37(20):2714-2727 - PubMed
  66. Genome Biol. 2014 Feb 03;15(2):R29 - PubMed
  67. Cancer Discov. 2021 May;11(5):1082-1099 - PubMed
  68. Nat Rev Dis Primers. 2016 Nov 10;2:16078 - PubMed
  69. Genes Dev. 2009 May 15;23(10):1171-6 - PubMed
  70. Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2259-64 - PubMed
  71. Cancer. 2016 Jan 1;122(1):20-33 - PubMed
  72. Nat Med. 2014 Dec;20(12):1394-6 - PubMed
  73. Cell. 2008 Jun 13;133(6):1106-17 - PubMed
  74. Cell Rep. 2017 May 23;19(8):1669-1684 - PubMed
  75. Cell Res. 2007 Oct;17(10):850-7 - PubMed
  76. J Clin Invest. 2018 Jan 2;128(1):446-462 - PubMed
  77. Cancer Res. 2016 Nov 15;76(22):6520-6532 - PubMed
  78. Nature. 2008 Feb 14;451(7180):796-801 - PubMed
  79. Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7 - PubMed
  80. Nature. 2013 Oct 17;502(7471):333-339 - PubMed
  81. Cancer Res. 2019 Nov 15;79(22):5849-5859 - PubMed
  82. Nat Commun. 2020 Nov 16;11(1):5823 - PubMed
  83. Cancer Cell. 2020 Apr 13;37(4):514-529 - PubMed
  84. Curr Opin Genet Dev. 2016 Feb;36:59-67 - PubMed
  85. Cancer Discov. 2015 Nov;5(11):1210-23 - PubMed
  86. PLoS One. 2012;7(12):e51407 - PubMed
  87. Bioinformatics. 2009 Aug 15;25(16):2078-9 - PubMed
  88. Mol Cell. 2004 Dec 3;16(5):831-7 - PubMed
  89. Nat Rev Mol Cell Biol. 2013 Aug;14(8):518-28 - PubMed
  90. Mol Cell. 2001 Jul;8(1):105-13 - PubMed
  91. Nat Rev Cancer. 2020 Feb;20(2):74-88 - PubMed
  92. Mol Cell. 2008 Nov 21;32(4):503-18 - PubMed
  93. Bioinformatics. 2010 Mar 15;26(6):841-2 - PubMed
  94. Cancer Res. 2008 Apr 15;68(8):2599-609 - PubMed
  95. EMBO J. 2013 May 15;32(10):1393-408 - PubMed
  96. Haematologica. 2017 Feb;102(2):373-380 - PubMed
  97. Nature. 2019 Aug;572(7771):676-680 - PubMed
  98. Carcinogenesis. 2014 Nov;35(11):2404-14 - PubMed
  99. J Biol Chem. 2014 Jun 27;289(26):18302-13 - PubMed
  100. Genes Chromosomes Cancer. 2008 Oct;47(10):819-34 - PubMed
  101. EMBO J. 2003 Oct 15;22(20):5323-35 - PubMed
  102. Nat Genet. 2018 Jan;50(1):73-82 - PubMed
  103. Nucleic Acids Res. 2009 Jul;37(Web Server issue):W202-8 - PubMed
  104. N Engl J Med. 2010 Jun 10;362(23):2202-11 - PubMed
  105. Genes Dev. 2011 Aug 1;25(15):1583-8 - PubMed
  106. Cell Rep. 2014 Nov 6;9(3):1163-70 - PubMed
  107. Front Oncol. 2013 Jan 25;3:1 - PubMed

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