ZFIN ID: ZDB-PUB-180214-20
Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma
Yu, Y., Schleich, K., Yue, B., Ji, S., Lohneis, P., Kemper, K., Silvis, M.S., Qutob, N., van Rooijen, E., Werner-Klein, M., Li, L., Dhawan, D., Meierjohann, S., Reimann, M., Elkahloun, A., Treitschke, S., Dörken, B., Speck, C., Mallette, F.A., Zon, L.I., Holmen, S.L., Peeper, D.S., Samuels, Y., Schmitt, C.A., Lee, S.
Date: 2018
Source: Cancer Cell   33: 322-336.e8 (Journal)
Registered Authors: van Rooijen, Ellen, Zon, Leonard I.
Keywords: H3K9, JMJD2C, LSD1, Ras/Braf, animal models, cellular senescence, histone demethylation, melanoma, patient-derived xenograft, targeted therapy
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
PubMed: 29438700 Full text @ Cancer Cell
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.