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| Status |
Public on Sep 11, 2023 |
| Title |
HEY1-NCOA2 interacts with RUNX2 to induce mesenchymal chondrosarcoma [ChIP-seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Mesenchymal chondrosarcoma is a high-grade malignant neoplasm characterized by biphasic growth of poorly differentiated small round cells and well differentiated cartilage. Mesenchymal chondrosarcoma affects adolescents and young adults, and the HEY1-NCOA2 fusion gene is causally associated with most cases. Here we generate a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic chondrogenic progenitors followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation, typical to human mesenchymal chondrosarcoma. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses indicated frequent inclusion of the RUNX DNA consensus sequences within HEY1-NCOA2-binding peaks. Runx2 that is important for differentiation and proliferation of the chondrocytic lineage is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. This interaction promotes repression of Runx2 target genes such as Adamts4 and Mmp13 to suppress chondrocytic differentiation and cell growth of tumors, and treatment with the HDAC inhibitor Panobinostat abrogates the repression activity of HEY1-NCOA2 and Runx2 to inhibit tumor growth both in vitro and in vivo. These results demonstrate that HEY1-NCOA2 expression induces malignant transformation of chondrogenic progenitors by modulating the RUNX2-regulated transcriptional program.
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| Overall design |
HEY1-NCOA2 was introduced by retrovirus-mediated gene transfer into mouse chondrogenic progenitors followed by subcutaneous transplantation of the cells. Subcutaneous tumors were subjected to cell culture. ChIP-seq analysis with various antibodies.
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| Contributor(s) |
Teramura Y, Tanaka M, Nakamura T |
| Citation(s) |
37212282 |
| Submission date |
Dec 21, 2020 |
| Last update date |
Sep 12, 2023 |
| Contact name |
Takuro Nakamura |
| E-mail(s) |
takuro-ind@umin.net
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| Phone |
81-3-3570-0462
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| Organization name |
Japanese Foundation for Cancer Research
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| Department |
The Cancer Institute
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| Lab |
Carcinogenesis
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| Street address |
3-8-31 Ariake, Koto-ku
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| City |
Tokyo |
| ZIP/Postal code |
135-8550 |
| Country |
Japan |
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| Platforms (1) |
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| Samples (11)
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| This SubSeries is part of SuperSeries: |
| GSE163588 |
HEY1-NCOA2 interacts with RUNX2 to induce mesenchymal chondrosarcoma |
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| Relations |
| BioProject |
PRJNA686877 |
| SRA |
SRP298682 |
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