Details

Autor(en) / Beteiligte

• Yu, Yong
• Schleich, Kolja
• Yue, Bin
• Ji, Sujuan
• Lohneis, Philipp
• Kemper, Kristel
• Silvis, Mark R.
• Qutob, Nouar
• van Rooijen, Ellen
• Werner-Klein, Melanie
• Li, Lianjie
• Dhawan, Dhriti
• Meierjohann, Svenja
• Reimann, Maurice
• Elkahloun, Abdel
• Treitschke, Steffi
• Dörken, Bernd
• Speck, Christian
• Mallette, Frédérick A.
• Zon, Leonard I.
• Holmen, Sheri L.
• Peeper, Daniel S.
• Samuels, Yardena
• Schmitt, Clemens A.
• Lee, Soyoung

Titel

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

Ist Teil von

• Cancer cell, 2018-02, Vol.33 (2), p.322-336.e8

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •H3K9me3-active demethylases like LSD1 or JMJD2C disable oncogene-induced senescence•LSD1 or JMJD2C cooperate with activated Braf in animal models of melanomagenesis•Human melanoma samples co-overexpress structurally unrelated H3K9 demethylases•H3K9 demethylase targeting blocks melanoma growth by restoring senescence Yu et al. show that two different types of histone H3 lysine 9 (H3K9) demethylases, LSD1 and JMJD2C, disable oncogenic Ras- or Braf-induced senescence by enabling the expression of E2F target genes, which permits transformation. Inhibition of the H3K9 demethylases restores senescence and controls tumor growth.