SS18-SSX drives CREB activation in synovial sarcoma.
666-15
BMS-754807
CREB
SS18-SSX
Synovial sarcoma
Journal
Cellular oncology (Dordrecht)
ISSN: 2211-3436
Titre abrégé: Cell Oncol (Dordr)
Pays: Netherlands
ID NLM: 101552938
Informations de publication
Date de publication:
Jun 2022
Jun 2022
Historique:
accepted:
08
04
2022
pubmed:
14
5
2022
medline:
15
6
2022
entrez:
13
5
2022
Statut:
ppublish
Résumé
Synovial sarcoma (SySa) is a rare soft tissue tumor characterized by a reciprocal t(X;18) translocation. The chimeric SS18-SSX fusion protein represents the major driver of the disease, acting as aberrant transcriptional dysregulator. Oncogenic mechanisms whereby SS18-SSX mediates sarcomagenesis are incompletely understood, and strategies to selectively target SySa cells remain elusive. Based on results of Phospho-Kinase screening arrays, we here investigate the functional and therapeutic relevance of the transcription factor CREB in SySa tumorigenesis. Immunohistochemistry of phosphorylated CREB and its downstream targets (Rb, Cyclin D1, PCNA, Bcl-xL and Bcl-2) was performed in a large cohort of SySa. Functional aspects of CREB activity, including SS18-SSX driven circuits involved in CREB activation, were analyzed in vitro employing five SySa cell lines and a mesenchymal stem cell model. CREB mediated transcriptional activity was modulated by RNAi-mediated knockdown and small molecule inhibitors (666-15, KG-501, NASTRp and Ro 31-8220). Anti-proliferative effects of the CREB inhibitor 666-15 were tested in SySa avian chorioallantoic membrane and murine xenograft models in vivo. We show that CREB is phosphorylated and activated in SySa, accompanied by downstream target expression. Human mesenchymal stem cells engineered to express SS18-SSX promote CREB expression and phosphorylation. Conversely, RNAi-mediated knockdown of SS18-SSX impairs CREB phosphorylation in SySa cells. Inhibition of CREB activity reduces downstream target expression, accompanied by suppression of SySa cell proliferation and induction of apoptosis in vitro and in vivo. In conclusion, our data underline an essential role of CREB in SySa tumorigenesis and provides evidence for molecular targeted therapies.
Identifiants
pubmed: 35556229
doi: 10.1007/s13402-022-00673-w
pii: 10.1007/s13402-022-00673-w
pmc: PMC9187574
doi:
Substances chimiques
Oncogene Proteins, Fusion
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
399-413Subventions
Organisme : deutsche forschungsgemeinschaft
ID : HA4441/2-1
Organisme : wilhelm sander-stiftung
ID : 2016.099.1
Organisme : medizinische fakultät, westfälische wilhelms-universität münster
ID : HU121421
Organisme : medizinische fakultät, westfälische wilhelms-universität münster
ID : TR121716
Organisme : medizinische fakultät, westfälische wilhelms-universität münster
ID : TR122011
Informations de copyright
© 2022. The Author(s).
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