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

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

doi:https://doi.org/10.1016/j.ccell.2018.01.002

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

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

Department of Molecular Cell Biology

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	322-336.e8
Number of pages	23
Journal	Cancer Cell
Volume	33
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2018.01.002
State	Published - 12 Feb 2018

All Science Journal Classification (ASJC) codes

Oncology
Cell Biology
Cancer Research

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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., ... Lee, S. (2018). Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma. Cancer Cell, 33(2), 322-336.e8. https://doi.org/10.1016/j.ccell.2018.01.002

@article{888de666e48646d0b9afadf46c737729,

title = "Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma",

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.",

author = "Yong Yu and Kolja Schleich and Bin Yue and Sujuan Ji and Philipp Lohneis and Kristel Kemper and Silvis, {Mark S} and Nouar Qutob and {van Rooijen}, Ellen and Melanie Werner-Klein and Lianjie Li and Dhriti Dhawan and Svenja Meierjohann and Maurice Reimann and Abdel Elkahloun and Steffi Treitschke and Bernd D{\"o}rken and Christian Speck and Mallette, {Fr{\'e}d{\'e}rick A} and Zon, {Leonard I} and Holmen, {Sheri L} and Peeper, {Daniel S} and Yardena Samuels and Schmitt, {Clemens A} and Soyoung Lee",

note = "We thank T. Jacks, T. Jenuwein, P. Khavari, S. Lowe, O. Fernandes-Capetillo, G. Willimsky, and M.J. Jager for reagents and mice, E. Berg, K. Reimers, N. Burbach, A. Herrmann, and S. Ma{\ss}wig as well as the Intervention Unit at the Netherlands Cancer Institute for technical assistance, and members of the Schmitt lab for discussions and editorial advice. This work was supported by grants from the Deutsche Forschungsgemeinschaft (TRR 54) and the German Cancer Consortium (Deutsches Konsortium fur Translationale Krebs-forschung [DKTK]) to C. A. S. and S. L.; Wilhelm Sander Foundation (2015.016.1) to M. W.-K.; NIH funding (R01 no. CA103846), a market readiness assistance grant, and the Ellison Foundation to L. I. Z.; Chinese Scholarship Council stipends to Y. Y., B. Y., and L. L.; a Berlin School of Integrative Oncology (BSIO) stipend to D.D.; ERC (StG-335377) to Y. S.; and the Canadian Institutes of Health Research (MOP-133442) to F. A. M. Author Contributions: Conducting Experiments, Y. Y., B. Y., S. J., P. L., K. K., M. R. S., E. v. R., L. L., D. D., S. T., M. R., and F. A. M.; Conceptual Input and Supervision, M. W.-K., C. S., B. D., S. M., L. I. Z., F. A. M., S. L. H., D. S. P., Y. S., C. A. S., and S. L.; Data Analysis, A. E., N. Q., and K. S.; Project Design and Writing, C. A. S. and S. L.",

year = "2018",

month = feb,

day = "12",

doi = "https://doi.org/10.1016/j.ccell.2018.01.002",

language = "الإنجليزيّة",

volume = "33",

pages = "322--336.e8",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

}

Yu, Y, Schleich, K, Yue, B, Ji, S, Lohneis, P, Kemper, K, Silvis, MS, 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, vol. 33, no. 2, pp. 322-336.e8. https://doi.org/10.1016/j.ccell.2018.01.002

TY - JOUR

T1 - Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma

AU - Yu, Yong

AU - Schleich, Kolja

AU - Yue, Bin

AU - Ji, Sujuan

AU - Lohneis, Philipp

AU - Kemper, Kristel

AU - Silvis, Mark S

AU - Qutob, Nouar

AU - van Rooijen, Ellen

AU - Werner-Klein, Melanie

AU - Li, Lianjie

AU - Dhawan, Dhriti

AU - Meierjohann, Svenja

AU - Reimann, Maurice

AU - Elkahloun, Abdel

AU - Treitschke, Steffi

AU - Dörken, Bernd

AU - Speck, Christian

AU - Mallette, Frédérick A

AU - Zon, Leonard I

AU - Holmen, Sheri L

AU - Peeper, Daniel S

AU - Samuels, Yardena

AU - Schmitt, Clemens A

AU - Lee, Soyoung

N1 - We thank T. Jacks, T. Jenuwein, P. Khavari, S. Lowe, O. Fernandes-Capetillo, G. Willimsky, and M.J. Jager for reagents and mice, E. Berg, K. Reimers, N. Burbach, A. Herrmann, and S. Maßwig as well as the Intervention Unit at the Netherlands Cancer Institute for technical assistance, and members of the Schmitt lab for discussions and editorial advice. This work was supported by grants from the Deutsche Forschungsgemeinschaft (TRR 54) and the German Cancer Consortium (Deutsches Konsortium fur Translationale Krebs-forschung [DKTK]) to C. A. S. and S. L.; Wilhelm Sander Foundation (2015.016.1) to M. W.-K.; NIH funding (R01 no. CA103846), a market readiness assistance grant, and the Ellison Foundation to L. I. Z.; Chinese Scholarship Council stipends to Y. Y., B. Y., and L. L.; a Berlin School of Integrative Oncology (BSIO) stipend to D.D.; ERC (StG-335377) to Y. S.; and the Canadian Institutes of Health Research (MOP-133442) to F. A. M. Author Contributions: Conducting Experiments, Y. Y., B. Y., S. J., P. L., K. K., M. R. S., E. v. R., L. L., D. D., S. T., M. R., and F. A. M.; Conceptual Input and Supervision, M. W.-K., C. S., B. D., S. M., L. I. Z., F. A. M., S. L. H., D. S. P., Y. S., C. A. S., and S. L.; Data Analysis, A. E., N. Q., and K. S.; Project Design and Writing, C. A. S. and S. L.

PY - 2018/2/12

Y1 - 2018/2/12

N2 - 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.

AB - 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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U2 - https://doi.org/10.1016/j.ccell.2018.01.002

DO - https://doi.org/10.1016/j.ccell.2018.01.002

M3 - مقالة

C2 - 29438700

SN - 1535-6108

VL - 33

SP - 322-336.e8

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

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

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