NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma
Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite advances in therapeutic management and immunotherapy, the 5-year survival rate for head and neck cancer remains at ~66% of all diagnosed cases. A better definition of drivers of HPV-negative HNS...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-02-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-024-01842-6 |
| _version_ | 1797275860847296512 |
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| author | Iuliia Topchu Igor Bychkov Demirkan Gursel Petr Makhov Yanis Boumber |
| author_facet | Iuliia Topchu Igor Bychkov Demirkan Gursel Petr Makhov Yanis Boumber |
| author_sort | Iuliia Topchu |
| collection | DOAJ |
| description | Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite advances in therapeutic management and immunotherapy, the 5-year survival rate for head and neck cancer remains at ~66% of all diagnosed cases. A better definition of drivers of HPV-negative HNSCC that are targetable points of tumor vulnerability could lead to significant clinical advances. NSD1 is a histone methyltransferase that catalyzes histone H3 lysine 36 di-methylation (H3K36me2); mutations inactivating NSD1 have been linked to improved outcomes in HNSCC. In this study, we show that NSD1 induces H3K36me2 levels in HNSCC and that the depletion of NSD1 reduces HNSCC of cell growth in vitro and in vivo. We also find that NSD1 strongly promotes activation of the Akt/mTORC1 signaling pathway. NSD1 depletion in HNSCC induces an autophagic gene program activation, causes accumulation of the p62 and LC3B-II proteins, and decreases the autophagic signaling protein ULK1 at both protein and mRNA levels. Reflecting these signaling defects, the knockdown of NSD1 disrupts autophagic flux in HNSCC cells. Taken together, these data identify positive regulation of Akt/mTORC1 signaling and autophagy as novel NSD1 functions in HNSCC, suggesting that NSD1 may be of value as a therapeutic target in this cancer. |
| first_indexed | 2024-03-07T15:20:06Z |
| format | Article |
| id | doaj.art-8cb8a5b5947c41198dc5e01242248f78 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-07T15:20:06Z |
| publishDate | 2024-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-8cb8a5b5947c41198dc5e01242248f782024-03-05T17:41:47ZengNature Publishing GroupCell Death Discovery2058-77162024-02-0110111310.1038/s41420-024-01842-6NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinomaIuliia Topchu0Igor Bychkov1Demirkan Gursel2Petr Makhov3Yanis Boumber4Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Division of Hematology/Oncology, Northwestern UniversityRobert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Division of Hematology/Oncology, Northwestern UniversityPathology Core Facility, Feinberg School of Medicine, Northwestern UniversityCancer Signaling and Microenvironment Program, Fox Chase Cancer CenterRobert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Division of Hematology/Oncology, Northwestern UniversityAbstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite advances in therapeutic management and immunotherapy, the 5-year survival rate for head and neck cancer remains at ~66% of all diagnosed cases. A better definition of drivers of HPV-negative HNSCC that are targetable points of tumor vulnerability could lead to significant clinical advances. NSD1 is a histone methyltransferase that catalyzes histone H3 lysine 36 di-methylation (H3K36me2); mutations inactivating NSD1 have been linked to improved outcomes in HNSCC. In this study, we show that NSD1 induces H3K36me2 levels in HNSCC and that the depletion of NSD1 reduces HNSCC of cell growth in vitro and in vivo. We also find that NSD1 strongly promotes activation of the Akt/mTORC1 signaling pathway. NSD1 depletion in HNSCC induces an autophagic gene program activation, causes accumulation of the p62 and LC3B-II proteins, and decreases the autophagic signaling protein ULK1 at both protein and mRNA levels. Reflecting these signaling defects, the knockdown of NSD1 disrupts autophagic flux in HNSCC cells. Taken together, these data identify positive regulation of Akt/mTORC1 signaling and autophagy as novel NSD1 functions in HNSCC, suggesting that NSD1 may be of value as a therapeutic target in this cancer.https://doi.org/10.1038/s41420-024-01842-6 |
| spellingShingle | Iuliia Topchu Igor Bychkov Demirkan Gursel Petr Makhov Yanis Boumber NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma Cell Death Discovery |
| title | NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma |
| title_full | NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma |
| title_fullStr | NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma |
| title_full_unstemmed | NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma |
| title_short | NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma |
| title_sort | nsd1 supports cell growth and regulates autophagy in hpv negative head and neck squamous cell carcinoma |
| url | https://doi.org/10.1038/s41420-024-01842-6 |
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