Journal
CANCER CELL
Volume 33, Issue 2, Pages 322-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.01.002
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Funding
- Deutsche Forschungsgemeinschaft [TRR 54]
- German Cancer Consortium (Deutsches Konsortium fur Translationale Krebsforschung [DKTK])
- Wilhelm Sander Foundation [2015.016.1]
- NIH [CA103846]
- Ellison Foundation
- Chinese Scholarship Council
- Berlin School of Integrative Oncology (BSIO)
- ERC [StG-335377]
- Canadian Institutes of Health Research [MOP-133442]
- BBSRC [BB/M003760/1, BB/N000323/1] Funding Source: UKRI
- MRC [MC_U120085811] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/M003760/1, BB/N000323/1] Funding Source: researchfish
- Medical Research Council [MC_U120085811] Funding Source: researchfish
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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.
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