A functional genetic screen identifies the Mediator complex as essential for SSX2-induced senescence
Date
2019
Authors
Brückmann, N.H.
Bennedsen, S.N.
Duijf, P.H.G.
Terp, M.G.
Thomassen, M.
Larsen, M.
Pedersen, C.B.
Kruse, T.
Alcaraz, N.
Ditzel, H.J.
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Journal article
Citation
Cell Death and Disease, 2019; 10(11, article no. 841):1-12
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Abstract
The senescence response to oncogenes is believed to be a barrier to oncogenic transformation in premalignant lesions, and describing the mechanisms by which tumor cells evade this response is important for early diagnosis and treatment. The male germ cell-associated protein SSX2 is ectopically expressed in many types of cancer and is functionally involved in regulating chromatin structure and supporting cell proliferation. Similar to many well characterized oncogenes, SSX2 has the ability to induce senescence in cells. In this study, we performed a function algenetic screen to identify proteins implicated in SSX2-induced senescence and identified several subunits of the Mediator complex, which is central in regulating RNA polymerase-mediated transcription. Further experiments showed that reduced levels of MED1, MED4, and MED14 perturbed the development of senescence in SSX2-expressing cells.
In contrast, knockdown of MED1 did not prevent development of B-Raf- and Epirubicin-induced senescence, suggesting that Mediator may be specifically linked to the cellular functions of SSX2 that may lead to development of senescence or be central in a SSX2-specific senescence response. Indeed, immunostaining of melanoma tumors, which often express SSX proteins, exhibited altered levels of MED1 compared to benign nevi. Similarly, RNA-seq analysis suggested that MED1, MED4, and MED14 were downregulated in some tumors, while upregulated in others. In conclusion, our study reveals the Mediator complex as essential for SSX2-induced senescence and suggests that changes in Mediator activity could be instrumental for tumorigenesis.
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Data source: Supplementary information, https://doi.org/10.1038/s41419-019-2068-1
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Copyright 2019 The Author(s) This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. (http://creativecommons.org/licenses/by/4.0/)