PUBLICATION

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

Authors
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.
ID
ZDB-PUB-180214-20
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
Abstract
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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes
This article is corrected by ZDB-PUB-220906-102 .