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Targeting the senescence-overriding cooperative activity of structurally unrelated H3K9 demethylases in melanoma

Authors

  • Y. Yu
  • K. Schleich
  • B. Yue
  • S. Ji
  • P. Lohneis
  • K. Kemper
  • M.S. Silvis
  • N. Qutob
  • E. van Rooijen
  • M. Werner-Klein
  • L. Li
  • D. Dhawan
  • S. Meierjohann
  • M. Reimann
  • A. Elkahloun
  • S. Treitschke
  • B. Dörken
  • C. Speck
  • F.A. Mallette
  • L.I. Zon
  • S.L. Holmen
  • D.S. Peeper
  • Y. Samuels
  • C.A. Schmitt
  • S. Lee

Journal

  • Cancer Cell

Citation

  • Cancer Cell 33 (2): 322-336

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.


DOI

doi:10.1016/j.ccell.2018.01.002