Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma

Cancer Cell. 2018 Feb 12;33(2):322-336.e8. doi: 10.1016/j.ccell.2018.01.002.


Oncogene-induced senescence, e.g., in melanocytic nevi, terminates the expansion of pre-malignant cells via transcriptional silencing of proliferation-related genes due to decoration of their promoters with repressive trimethylated histone H3 lysine 9 (H3K9) marks. We show here that structurally distinct H3K9-active demethylases-the lysine-specific demethylase-1 (LSD1) and several Jumonji C domain-containing moieties (such as JMJD2C)-disable senescence and permit Ras/Braf-evoked transformation. In mouse and zebrafish models, enforced LSD1 or JMJD2C expression promoted Braf-V600E-driven melanomagenesis. A large subset of established melanoma cell lines and primary human melanoma samples presented with a collective upregulation of related and unrelated H3K9 demethylase activities, whose targeted inhibition restored senescence, even in Braf inhibitor-resistant melanomas, evoked secondary immune effects and controlled tumor growth in vivo.

Keywords: H3K9; JMJD2C; LSD1; Ras/Braf; animal models; cellular senescence; histone demethylation; melanoma; patient-derived xenograft; targeted therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Histone Demethylases / genetics*
  • Histones / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics*
  • Lysine / genetics
  • Lysine / metabolism
  • Melanoma / genetics*
  • Methylation
  • Mice, Nude
  • Promoter Regions, Genetic / genetics


  • Histones
  • KDM4C protein, human
  • Histone Demethylases
  • Jmjd2c protein, mouse
  • Jumonji Domain-Containing Histone Demethylases
  • KDM1a protein, mouse
  • KDM1A protein, human
  • Lysine