SMYD3 drives cell cycle and epithelial-mesenchymal transition pathways through dual gene transcriptional repression and activation in HPV-negative head and neck cancer
Abstract Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type in the world and is associated with an overall poor prognosis. The protein methyltransferase SET and MYND domain-containing 3 (SMYD3), which trimethylates H3K4, activates g...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-83396-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841544713801302016 |
|---|---|
| author | Madhavi Murali Abbas Saeed Sohyoung Kim Kyunghee Burkitt Hui Cheng Arfa Moshiri Jawad Akhtar Daniel Tsai Marie Luff Baktiar Karim Vassiliki Saloura |
| author_facet | Madhavi Murali Abbas Saeed Sohyoung Kim Kyunghee Burkitt Hui Cheng Arfa Moshiri Jawad Akhtar Daniel Tsai Marie Luff Baktiar Karim Vassiliki Saloura |
| author_sort | Madhavi Murali |
| collection | DOAJ |
| description | Abstract Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type in the world and is associated with an overall poor prognosis. The protein methyltransferase SET and MYND domain-containing 3 (SMYD3), which trimethylates H3K4, activates gene transcription and enhances several oncogenic pathways, including epithelial-mesenchymal transition and cell cycle related pathways, in various cancer types. It was also recently shown that SMYD3 is overexpressed in HPV-negative HNSCC, and represses the expression of type I IFN response genes, contributing to resistance to anti-PD-1 checkpoint blockade in this disease. In this study, we show that SMYD3 depletion using siRNA interference or CRISPR decreases cellular proliferation and clonal capacity, induces cell cycle arrest and decreases the invasive potential of HPV-negative HNSCC cell lines. Accordingly, xenografts of SMYD3 knockout tumors derived from a human HPV-negative HNSCC cell line grew significantly slower compared to control tumors in mice. Genome-wide mapping for SMYD3 and H3K4me3 in HPV-negative HNSCC cells using cleavage under targets and release using nuclease (CUT&RUN) assays identified direct downstream gene targets regulated by SMYD3, including cell cycle- and EMT-promoting genes. This study provides insights into the epigenetic role of SMYD3 as an oncogene in HPV-negative HNSCC and supports SMYD3 as a rational therapeutic target in HPV-negative HNSCC. |
| format | Article |
| id | doaj-art-0401378147c249989787802f29615ca4 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-0401378147c249989787802f29615ca42025-01-12T12:20:35ZengNature PortfolioScientific Reports2045-23222025-01-0115111610.1038/s41598-024-83396-2SMYD3 drives cell cycle and epithelial-mesenchymal transition pathways through dual gene transcriptional repression and activation in HPV-negative head and neck cancerMadhavi Murali0Abbas Saeed1Sohyoung Kim2Kyunghee Burkitt3Hui Cheng4Arfa Moshiri5Jawad Akhtar6Daniel Tsai7Marie Luff8Baktiar Karim9Vassiliki Saloura10Thoracic and GI Malignancies Branch, National Institutes of HealthThoracic and GI Malignancies Branch, National Institutes of HealthLaboratory of Receptor Biology and Gene Expression, National Cancer InstituteThoracic and GI Malignancies Branch, National Institutes of HealthNational Institute on Deafness and Other Communication Disorders, NIHThoracic and GI Malignancies Branch, National Institutes of HealthThoracic and GI Malignancies Branch, National Institutes of HealthThoracic and GI Malignancies Branch, National Institutes of HealthThoracic and GI Malignancies Branch, National Institutes of HealthMolecular Histopathology Laboratory, National Institutes of HealthThoracic and GI Malignancies Branch, National Institutes of HealthAbstract Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type in the world and is associated with an overall poor prognosis. The protein methyltransferase SET and MYND domain-containing 3 (SMYD3), which trimethylates H3K4, activates gene transcription and enhances several oncogenic pathways, including epithelial-mesenchymal transition and cell cycle related pathways, in various cancer types. It was also recently shown that SMYD3 is overexpressed in HPV-negative HNSCC, and represses the expression of type I IFN response genes, contributing to resistance to anti-PD-1 checkpoint blockade in this disease. In this study, we show that SMYD3 depletion using siRNA interference or CRISPR decreases cellular proliferation and clonal capacity, induces cell cycle arrest and decreases the invasive potential of HPV-negative HNSCC cell lines. Accordingly, xenografts of SMYD3 knockout tumors derived from a human HPV-negative HNSCC cell line grew significantly slower compared to control tumors in mice. Genome-wide mapping for SMYD3 and H3K4me3 in HPV-negative HNSCC cells using cleavage under targets and release using nuclease (CUT&RUN) assays identified direct downstream gene targets regulated by SMYD3, including cell cycle- and EMT-promoting genes. This study provides insights into the epigenetic role of SMYD3 as an oncogene in HPV-negative HNSCC and supports SMYD3 as a rational therapeutic target in HPV-negative HNSCC.https://doi.org/10.1038/s41598-024-83396-2 |
| spellingShingle | Madhavi Murali Abbas Saeed Sohyoung Kim Kyunghee Burkitt Hui Cheng Arfa Moshiri Jawad Akhtar Daniel Tsai Marie Luff Baktiar Karim Vassiliki Saloura SMYD3 drives cell cycle and epithelial-mesenchymal transition pathways through dual gene transcriptional repression and activation in HPV-negative head and neck cancer Scientific Reports |
| title | SMYD3 drives cell cycle and epithelial-mesenchymal transition pathways through dual gene transcriptional repression and activation in HPV-negative head and neck cancer |
| title_full | SMYD3 drives cell cycle and epithelial-mesenchymal transition pathways through dual gene transcriptional repression and activation in HPV-negative head and neck cancer |
| title_fullStr | SMYD3 drives cell cycle and epithelial-mesenchymal transition pathways through dual gene transcriptional repression and activation in HPV-negative head and neck cancer |
| title_full_unstemmed | SMYD3 drives cell cycle and epithelial-mesenchymal transition pathways through dual gene transcriptional repression and activation in HPV-negative head and neck cancer |
| title_short | SMYD3 drives cell cycle and epithelial-mesenchymal transition pathways through dual gene transcriptional repression and activation in HPV-negative head and neck cancer |
| title_sort | smyd3 drives cell cycle and epithelial mesenchymal transition pathways through dual gene transcriptional repression and activation in hpv negative head and neck cancer |
| url | https://doi.org/10.1038/s41598-024-83396-2 |
| work_keys_str_mv | AT madhavimurali smyd3drivescellcycleandepithelialmesenchymaltransitionpathwaysthroughdualgenetranscriptionalrepressionandactivationinhpvnegativeheadandneckcancer AT abbassaeed smyd3drivescellcycleandepithelialmesenchymaltransitionpathwaysthroughdualgenetranscriptionalrepressionandactivationinhpvnegativeheadandneckcancer AT sohyoungkim smyd3drivescellcycleandepithelialmesenchymaltransitionpathwaysthroughdualgenetranscriptionalrepressionandactivationinhpvnegativeheadandneckcancer AT kyungheeburkitt smyd3drivescellcycleandepithelialmesenchymaltransitionpathwaysthroughdualgenetranscriptionalrepressionandactivationinhpvnegativeheadandneckcancer AT huicheng smyd3drivescellcycleandepithelialmesenchymaltransitionpathwaysthroughdualgenetranscriptionalrepressionandactivationinhpvnegativeheadandneckcancer AT arfamoshiri smyd3drivescellcycleandepithelialmesenchymaltransitionpathwaysthroughdualgenetranscriptionalrepressionandactivationinhpvnegativeheadandneckcancer AT jawadakhtar smyd3drivescellcycleandepithelialmesenchymaltransitionpathwaysthroughdualgenetranscriptionalrepressionandactivationinhpvnegativeheadandneckcancer AT danieltsai smyd3drivescellcycleandepithelialmesenchymaltransitionpathwaysthroughdualgenetranscriptionalrepressionandactivationinhpvnegativeheadandneckcancer AT marieluff smyd3drivescellcycleandepithelialmesenchymaltransitionpathwaysthroughdualgenetranscriptionalrepressionandactivationinhpvnegativeheadandneckcancer AT baktiarkarim smyd3drivescellcycleandepithelialmesenchymaltransitionpathwaysthroughdualgenetranscriptionalrepressionandactivationinhpvnegativeheadandneckcancer AT vassilikisaloura smyd3drivescellcycleandepithelialmesenchymaltransitionpathwaysthroughdualgenetranscriptionalrepressionandactivationinhpvnegativeheadandneckcancer |