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

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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 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
Volume10
Issue number11
Number of pages12
ISSN2041-4889
DOIs
Publication statusPublished - 6. Nov 2019

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Neoplasms
Epirubicin
Proteins
Cell Aging
Nevus
Germ Cells
Melanoma
Down-Regulation
Cell Proliferation
RNA

Cite this

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title = "A functional genetic screen identifies the Mediator complex as essential for SSX2-induced senescence",
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 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.",
author = "Br{\"u}ckmann, {Nadine H} and Bennedsen, {Sofie N} and Duijf, {Pascal H G} and Terp, {Mikkel G} and Mads Thomassen and Martin Larsen and Pedersen, {Christina B} and Torben Kruse and Nicolas Alcaraz and Ditzel, {Henrik J} and Gjerstorff, {Morten F}",
year = "2019",
month = "11",
day = "6",
doi = "10.1038/s41419-019-2068-1",
language = "English",
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A functional genetic screen identifies the Mediator complex as essential for SSX2-induced senescence. / Brückmann, Nadine H; Bennedsen, Sofie N; Duijf, Pascal H G; Terp, Mikkel G; Thomassen, Mads; Larsen, Martin; Pedersen, Christina B; Kruse, Torben; Alcaraz, Nicolas; Ditzel, Henrik J; Gjerstorff, Morten F.

In: Cell Death & Disease, Vol. 10, No. 11, 841, 06.11.2019.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - A functional genetic screen identifies the Mediator complex as essential for SSX2-induced senescence

AU - Brückmann, Nadine H

AU - Bennedsen, Sofie N

AU - Duijf, Pascal H G

AU - Terp, Mikkel G

AU - Thomassen, Mads

AU - Larsen, Martin

AU - Pedersen, Christina B

AU - Kruse, Torben

AU - Alcaraz, Nicolas

AU - Ditzel, Henrik J

AU - Gjerstorff, Morten F

PY - 2019/11/6

Y1 - 2019/11/6

N2 - 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.

AB - 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.

U2 - 10.1038/s41419-019-2068-1

DO - 10.1038/s41419-019-2068-1

M3 - Journal article

C2 - 31695025

VL - 10

JO - Cell Death & Disease

JF - Cell Death & Disease

SN - 2041-4889

IS - 11

M1 - 841

ER -