A functional genetic screen identifies the Mediator complex as essential for SSX2-induced senescence

Nadine H Brückmann, Sofie N Bennedsen, Pascal H G Duijf, Mikkel G Terp, Mads Thomassen, Martin Larsen, Christina B Pedersen, Torben Kruse, Nicolas Alcaraz, Henrik J Ditzel, Morten F Gjerstorff*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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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 functional genetic 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.

Original languageEnglish
Article number841
JournalCell Death & Disease
Issue number11
Number of pages12
Publication statusPublished - 6. Nov 2019


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