Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma
Human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) represents a unique disease entity within head and neck cancer with rising incidence. Previous work has shown that alternative splicing events (ASEs) are prevalent in HPV+ OPSCC, but further validation is needed to under...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2020-09-01
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| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2020.1741757 |
| _version_ | 1827811557146361856 |
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| author | Theresa Guo Kristina Diana A. Zambo Fernando T. Zamuner Tingting Ou Christopher Hopkins Dylan Z. Kelley Hildegard A. Wulf Eli Winkler Rossin Erbe Ludmila Danilova Michael Considine David Sidransky Alexander Favorov Liliana Florea Elana J. Fertig Daria A. Gaykalova |
| author_facet | Theresa Guo Kristina Diana A. Zambo Fernando T. Zamuner Tingting Ou Christopher Hopkins Dylan Z. Kelley Hildegard A. Wulf Eli Winkler Rossin Erbe Ludmila Danilova Michael Considine David Sidransky Alexander Favorov Liliana Florea Elana J. Fertig Daria A. Gaykalova |
| author_sort | Theresa Guo |
| collection | DOAJ |
| description | Human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) represents a unique disease entity within head and neck cancer with rising incidence. Previous work has shown that alternative splicing events (ASEs) are prevalent in HPV+ OPSCC, but further validation is needed to understand the regulation of this process and its role in these tumours. In this study, eleven ASEs (GIT2, CTNNB1, MKNK2, MRPL33, SIPA1L3, SNHG6, SYCP2, TPRG1, ZHX2, ZNF331, and ELOVL1) were selected for validation from 109 previously published candidate ASEs to elucidate the post-transcriptional mechanisms of oncogenesis in HPV+ disease. In vitro qRT-PCR confirmed differential expression of 9 of 11 ASE candidates, and in silico analysis within the TCGA cohort confirmed 8 of 11 candidates. Six ASEs (MRPL33, SIPA1L3, SNHG6, TPRG1, ZHX2, and ELOVL1) showed significant differential expression across both methods. Further evaluation of chromatin modification revealed that ASEs strongly correlated with cancer-specific distribution of acetylated lysine 27 of histone 3 (H3K27ac). Subsequent epigenetic treatment of HPV+ HNSCC cell lines (UM-SCC-047 and UPCI-SCC-090) with JQ1 not only induced downregulation of cancer-specific ASE isoforms, but also growth inhibition in both cell lines. The UPCI-SCC-090 cell line, with greater ASE expression, also showed more significant growth inhibition after JQ1 treatment. This study confirms several novel cancer-specific ASEs in HPV+OPSCC and provides evidence for the role of chromatin modifications in regulation of alternative splicing in HPV+OPSCC. This highlights the role of epigenetic changes in the oncogenesis of HPV+OPSCC, which represents a unique, unexplored target for therapeutics that can alter the global post-transcriptional landscape. |
| first_indexed | 2024-03-11T23:06:34Z |
| format | Article |
| id | doaj.art-79cc2062bbdf4787af9bc92b175c4901 |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:06:34Z |
| publishDate | 2020-09-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-79cc2062bbdf4787af9bc92b175c49012023-09-21T13:09:23ZengTaylor & Francis GroupEpigenetics1559-22941559-23082020-09-0115995997110.1080/15592294.2020.17417571741757Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinomaTheresa Guo0Kristina Diana A. Zambo1Fernando T. Zamuner2Tingting Ou3Christopher Hopkins4Dylan Z. Kelley5Hildegard A. Wulf6Eli Winkler7Rossin Erbe8Ludmila Danilova9Michael Considine10David Sidransky11Alexander Favorov12Liliana Florea13Elana J. Fertig14Daria A. Gaykalova15Johns Hopkins University School of MedicineJohns Hopkins University School of MedicineJohns Hopkins University School of MedicineJohns Hopkins University School of MedicineJohns Hopkins University School of MedicineJohns Hopkins University School of MedicineJohns Hopkins University School of MedicineJohns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineJohns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineJohns Hopkins UniversityThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineJohns Hopkins University School of MedicineHuman papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) represents a unique disease entity within head and neck cancer with rising incidence. Previous work has shown that alternative splicing events (ASEs) are prevalent in HPV+ OPSCC, but further validation is needed to understand the regulation of this process and its role in these tumours. In this study, eleven ASEs (GIT2, CTNNB1, MKNK2, MRPL33, SIPA1L3, SNHG6, SYCP2, TPRG1, ZHX2, ZNF331, and ELOVL1) were selected for validation from 109 previously published candidate ASEs to elucidate the post-transcriptional mechanisms of oncogenesis in HPV+ disease. In vitro qRT-PCR confirmed differential expression of 9 of 11 ASE candidates, and in silico analysis within the TCGA cohort confirmed 8 of 11 candidates. Six ASEs (MRPL33, SIPA1L3, SNHG6, TPRG1, ZHX2, and ELOVL1) showed significant differential expression across both methods. Further evaluation of chromatin modification revealed that ASEs strongly correlated with cancer-specific distribution of acetylated lysine 27 of histone 3 (H3K27ac). Subsequent epigenetic treatment of HPV+ HNSCC cell lines (UM-SCC-047 and UPCI-SCC-090) with JQ1 not only induced downregulation of cancer-specific ASE isoforms, but also growth inhibition in both cell lines. The UPCI-SCC-090 cell line, with greater ASE expression, also showed more significant growth inhibition after JQ1 treatment. This study confirms several novel cancer-specific ASEs in HPV+OPSCC and provides evidence for the role of chromatin modifications in regulation of alternative splicing in HPV+OPSCC. This highlights the role of epigenetic changes in the oncogenesis of HPV+OPSCC, which represents a unique, unexplored target for therapeutics that can alter the global post-transcriptional landscape.http://dx.doi.org/10.1080/15592294.2020.1741757human papillomavirusoropharyngeal canceralternative splicingsuper-enhancers |
| spellingShingle | Theresa Guo Kristina Diana A. Zambo Fernando T. Zamuner Tingting Ou Christopher Hopkins Dylan Z. Kelley Hildegard A. Wulf Eli Winkler Rossin Erbe Ludmila Danilova Michael Considine David Sidransky Alexander Favorov Liliana Florea Elana J. Fertig Daria A. Gaykalova Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma Epigenetics human papillomavirus oropharyngeal cancer alternative splicing super-enhancers |
| title | Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma |
| title_full | Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma |
| title_fullStr | Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma |
| title_full_unstemmed | Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma |
| title_short | Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma |
| title_sort | chromatin structure regulates cancer specific alternative splicing events in primary hpv related oropharyngeal squamous cell carcinoma |
| topic | human papillomavirus oropharyngeal cancer alternative splicing super-enhancers |
| url | http://dx.doi.org/10.1080/15592294.2020.1741757 |
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