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YWHAE-NUTM2 oncoprotein regulates proliferation and cyclin D1 via RAF/MAPK and Hippo pathways
- Source :
- Oncogenesis, Vol 10, Iss 5, Pp 1-9 (2021), Oncogenesis
- Publication Year :
- 2021
- Publisher :
- Nature Publishing Group, 2021.
-
Abstract
- Endometrial stromal sarcoma (ESS) is the second most common subtype of uterine mesenchymal cancer, after leiomyosarcoma, and oncogenic fusion proteins are found in many ESS. Our previous studies demonstrated transforming properties and diagnostic relevance of the fusion oncoprotein YWHAE–NUTM2 in high-grade endometrial stromal sarcoma (HG-ESS) and showed that cyclin D1 is a diagnostic biomarker in these HG-ESS. However, YWHAE–NUTM2 mechanisms of oncogenesis and roles in cyclin D1 expression have not been characterized. In the current studies, we show YWHAE-NUTM2 complexes with both BRAF/RAF1 and YAP/TAZ in HG-ESS. These interactions are functionally relevant because YWHAE-NUTM2 knockdown in HG-ESS and other models inhibits RAF/MEK/MAPK phosphorylation, cyclin D1 expression, and cell proliferation. Further, cyclin D1 knockdown in HG-ESS dephosphorylates RB1 and inhibits proliferation. In keeping with these findings, we show that MEK and CDK4/6 inhibitors have anti-proliferative effects in HG-ESS, and combinations of these inhibitors have synergistic activity. These findings establish that YWHAE-NUTM2 regulates cyclin D1 expression and cell proliferation by dysregulating RAF/MEK/MAPK and Hippo/YAP-TAZ signaling pathways. Recent studies demonstrate Hippo/YAP-TAZ pathway aberrations in many sarcomas, but this is among the first studies to demonstrate a well-defined oncogenic mechanism as the cause of Hippo pathway dysregulation.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Cancer Research
Hippo signaling pathway
Gene knockdown
Endometrial stromal sarcoma
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Biology
medicine.disease
medicine.disease_cause
Article
03 medical and health sciences
Targeted therapies
030104 developmental biology
0302 clinical medicine
Cyclin D1
Endometrial cancer
030220 oncology & carcinogenesis
medicine
Cancer research
Signal transduction
Carcinogenesis
Molecular Biology
YWHAE
RC254-282
Subjects
Details
- Language :
- English
- ISSN :
- 21579024
- Volume :
- 10
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Oncogenesis
- Accession number :
- edsair.doi.dedup.....b1c153907e2f6d952648d7e15def840b