The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors
Abstract Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically. While surgery is the primary treatment for localized MPNST with a 61.9% overall survival rate, metastatic disease is often f...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-03-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-94517-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849392532251738112 |
|---|---|
| author | Imad Soukar Robert J. Fisher Sanjana Bhagavatula Marianne Collard Philip A. Cole Rhoda M. Alani |
| author_facet | Imad Soukar Robert J. Fisher Sanjana Bhagavatula Marianne Collard Philip A. Cole Rhoda M. Alani |
| author_sort | Imad Soukar |
| collection | DOAJ |
| description | Abstract Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically. While surgery is the primary treatment for localized MPNST with a 61.9% overall survival rate, metastatic disease is often fatal due to resistance to systemic therapies which underscores the urgent need for effective treatments. MPNSTs frequently harbor inactivating driver mutations in the PRC2 epigenetic repressor complex suggesting epigenetic therapies may represent a specific vulnerability in these tumors. Here, we investigate the role of the LSD1-HDAC1-CoREST (LHC) repressor complex in mediating MPNST tumor growth and progression. Our findings demonstrate that the LHC small molecule inhibitor, corin, induces apoptosis and significantly inhibits proliferation in MPNST cells. Transcriptomic analysis of corin-treated MPNST cells demonstrates specific increases in genes associated with axonogenesis and neuronal differentiation as well as altered extracellular matrix; additionally, corin treatment is shown to inhibit MPNST invasion in vitro. These results underscore the critical role of the LHC complex in facilitating MPNST growth and progression and suggest that targeting the LHC complex represents a promising therapeutic approach for this aggressive malignancy. |
| format | Article |
| id | doaj-art-84bcb9c0ee4f4a0f901ecda0e8e10a89 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-84bcb9c0ee4f4a0f901ecda0e8e10a892025-08-20T03:40:44ZengNature PortfolioScientific Reports2045-23222025-03-0115111210.1038/s41598-025-94517-wThe CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumorsImad Soukar0Robert J. Fisher1Sanjana Bhagavatula2Marianne Collard3Philip A. Cole4Rhoda M. Alani5Department of Dermatology, Boston University Chobanian and Avedisian School of MedicineDepartment of Dermatology, Boston University Chobanian and Avedisian School of MedicineDepartment of Dermatology, Boston University Chobanian and Avedisian School of MedicineDepartment of Dermatology, Boston University Chobanian and Avedisian School of MedicineDivision of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Brigham and Women’s HospitalDepartment of Dermatology, Boston University Chobanian and Avedisian School of MedicineAbstract Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically. While surgery is the primary treatment for localized MPNST with a 61.9% overall survival rate, metastatic disease is often fatal due to resistance to systemic therapies which underscores the urgent need for effective treatments. MPNSTs frequently harbor inactivating driver mutations in the PRC2 epigenetic repressor complex suggesting epigenetic therapies may represent a specific vulnerability in these tumors. Here, we investigate the role of the LSD1-HDAC1-CoREST (LHC) repressor complex in mediating MPNST tumor growth and progression. Our findings demonstrate that the LHC small molecule inhibitor, corin, induces apoptosis and significantly inhibits proliferation in MPNST cells. Transcriptomic analysis of corin-treated MPNST cells demonstrates specific increases in genes associated with axonogenesis and neuronal differentiation as well as altered extracellular matrix; additionally, corin treatment is shown to inhibit MPNST invasion in vitro. These results underscore the critical role of the LHC complex in facilitating MPNST growth and progression and suggest that targeting the LHC complex represents a promising therapeutic approach for this aggressive malignancy.https://doi.org/10.1038/s41598-025-94517-wCoRESTCorinHDACLSD1MPNSTEpigenetics |
| spellingShingle | Imad Soukar Robert J. Fisher Sanjana Bhagavatula Marianne Collard Philip A. Cole Rhoda M. Alani The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors Scientific Reports CoREST Corin HDAC LSD1 MPNST Epigenetics |
| title | The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors |
| title_full | The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors |
| title_fullStr | The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors |
| title_full_unstemmed | The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors |
| title_short | The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors |
| title_sort | corest complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors |
| topic | CoREST Corin HDAC LSD1 MPNST Epigenetics |
| url | https://doi.org/10.1038/s41598-025-94517-w |
| work_keys_str_mv | AT imadsoukar thecorestcomplexisatherapeuticvulnerabilityinmalignantperipheralnervesheathtumors AT robertjfisher thecorestcomplexisatherapeuticvulnerabilityinmalignantperipheralnervesheathtumors AT sanjanabhagavatula thecorestcomplexisatherapeuticvulnerabilityinmalignantperipheralnervesheathtumors AT mariannecollard thecorestcomplexisatherapeuticvulnerabilityinmalignantperipheralnervesheathtumors AT philipacole thecorestcomplexisatherapeuticvulnerabilityinmalignantperipheralnervesheathtumors AT rhodamalani thecorestcomplexisatherapeuticvulnerabilityinmalignantperipheralnervesheathtumors AT imadsoukar corestcomplexisatherapeuticvulnerabilityinmalignantperipheralnervesheathtumors AT robertjfisher corestcomplexisatherapeuticvulnerabilityinmalignantperipheralnervesheathtumors AT sanjanabhagavatula corestcomplexisatherapeuticvulnerabilityinmalignantperipheralnervesheathtumors AT mariannecollard corestcomplexisatherapeuticvulnerabilityinmalignantperipheralnervesheathtumors AT philipacole corestcomplexisatherapeuticvulnerabilityinmalignantperipheralnervesheathtumors AT rhodamalani corestcomplexisatherapeuticvulnerabilityinmalignantperipheralnervesheathtumors |