Yu Y, Schleich K, Yue B, Ji S, Lohneis P, Kemper K, Silvis MR, 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 FA, Zon LI, Holmen SL, Peeper DS, Samuels Y, Schmitt CA, Lee S. Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma. Cancer Cell. 2018 02 12; 33(2):322-336.e8.

Citation

Yu Y, Schleich K, Yue B, Ji S, Lohneis P, Kemper K, Silvis MR, 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 FA, Zon LI, Holmen SL, Peeper DS, Samuels Y, Schmitt CA, Lee S. 2018. Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma. Cancer cell. 33(2):322-336.e8. Pubmed: 29438700 DOI:S1535-6108(18)30002-3

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.

Related Faculty

Leonard Zon, M.D.

Zon Lab

The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.