Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells
Abstract Background The ST6Gal-I glycosyltransferase, which adds α2–6-linked sialic acids to N-glycosylated proteins is upregulated in a wide range of malignancies including ovarian cancer. Prior studies have shown that ST6Gal-I-mediated sialylation of select surface receptors remodels intracellular...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-10-01
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| Series: | Journal of Ovarian Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13048-019-0574-5 |
| _version_ | 1797966987088887808 |
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| author | Kaitlyn A. Dorsett Robert B. Jones Katherine E. Ankenbauer Anita B. Hjelmeland Susan L. Bellis |
| author_facet | Kaitlyn A. Dorsett Robert B. Jones Katherine E. Ankenbauer Anita B. Hjelmeland Susan L. Bellis |
| author_sort | Kaitlyn A. Dorsett |
| collection | DOAJ |
| description | Abstract Background The ST6Gal-I glycosyltransferase, which adds α2–6-linked sialic acids to N-glycosylated proteins is upregulated in a wide range of malignancies including ovarian cancer. Prior studies have shown that ST6Gal-I-mediated sialylation of select surface receptors remodels intracellular signaling to impart cancer stem cell (CSC) characteristics. However, the mechanisms that contribute to ST6Gal-I expression in stem-like cancer cells are poorly understood. Results Herein, we identify the master stem cell transcription factor, Sox2, as a novel regulator of ST6Gal-I expression. Interestingly, SOX2 and ST6GAL1 are located within the same tumor-associated amplicon, 3q26, and these two genes exhibit coordinate gains in copy number across multiple cancers including ~ 25% of ovarian serious adenocarcinomas. In conjunction with genetic co-amplification, our studies suggest that Sox2 directly binds the ST6GAL1 promoter to drive transcription. ST6Gal-I expression is directed by at least four distinct promoters, and we identified the P3 promoter as the predominant promoter utilized by ovarian cancer cells. Chromatin Immunoprecipitation (ChIP) assays revealed that Sox2 binds regions proximal to the P3 promoter. To confirm that Sox2 regulates ST6Gal-I expression, Sox2 was either overexpressed or knocked-down in various ovarian cancer cell lines. Sox2 overexpression induced an increase in ST6Gal-I mRNA and protein, as well as surface α2–6 sialylation, whereas Sox2 knock-down suppressed levels of ST6Gal-I mRNA, protein and surface α2–6 sialylation. Conclusions These data suggest a process whereby SOX2 and ST6GAL1 are coordinately amplified in cancer cells, with the Sox2 protein then binding the ST6GAL1 promoter to further augment ST6Gal-I expression. Our collective results provide new insight into mechanisms that upregulate ST6Gal-I expression in ovarian cancer cells, and also point to the possibility that some of the CSC characteristics commonly attributed to Sox2 may, in part, be mediated through the sialyltransferase activity of ST6Gal-I. |
| first_indexed | 2024-04-11T02:22:57Z |
| format | Article |
| id | doaj.art-b818a3a798914e8fa50cea2b13d78301 |
| institution | Directory Open Access Journal |
| issn | 1757-2215 |
| language | English |
| last_indexed | 2024-04-11T02:22:57Z |
| publishDate | 2019-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Ovarian Research |
| spelling | doaj.art-b818a3a798914e8fa50cea2b13d783012023-01-02T23:11:52ZengBMCJournal of Ovarian Research1757-22152019-10-0112111310.1186/s13048-019-0574-5Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cellsKaitlyn A. Dorsett0Robert B. Jones1Katherine E. Ankenbauer2Anita B. Hjelmeland3Susan L. Bellis4Department of Cell, Developmental and Integrative Biology, University of Alabama at BirminghamDepartment of Cell, Developmental and Integrative Biology, University of Alabama at BirminghamDepartment of Cell, Developmental and Integrative Biology, University of Alabama at BirminghamDepartment of Cell, Developmental and Integrative Biology, University of Alabama at BirminghamDepartment of Cell, Developmental and Integrative Biology, University of Alabama at BirminghamAbstract Background The ST6Gal-I glycosyltransferase, which adds α2–6-linked sialic acids to N-glycosylated proteins is upregulated in a wide range of malignancies including ovarian cancer. Prior studies have shown that ST6Gal-I-mediated sialylation of select surface receptors remodels intracellular signaling to impart cancer stem cell (CSC) characteristics. However, the mechanisms that contribute to ST6Gal-I expression in stem-like cancer cells are poorly understood. Results Herein, we identify the master stem cell transcription factor, Sox2, as a novel regulator of ST6Gal-I expression. Interestingly, SOX2 and ST6GAL1 are located within the same tumor-associated amplicon, 3q26, and these two genes exhibit coordinate gains in copy number across multiple cancers including ~ 25% of ovarian serious adenocarcinomas. In conjunction with genetic co-amplification, our studies suggest that Sox2 directly binds the ST6GAL1 promoter to drive transcription. ST6Gal-I expression is directed by at least four distinct promoters, and we identified the P3 promoter as the predominant promoter utilized by ovarian cancer cells. Chromatin Immunoprecipitation (ChIP) assays revealed that Sox2 binds regions proximal to the P3 promoter. To confirm that Sox2 regulates ST6Gal-I expression, Sox2 was either overexpressed or knocked-down in various ovarian cancer cell lines. Sox2 overexpression induced an increase in ST6Gal-I mRNA and protein, as well as surface α2–6 sialylation, whereas Sox2 knock-down suppressed levels of ST6Gal-I mRNA, protein and surface α2–6 sialylation. Conclusions These data suggest a process whereby SOX2 and ST6GAL1 are coordinately amplified in cancer cells, with the Sox2 protein then binding the ST6GAL1 promoter to further augment ST6Gal-I expression. Our collective results provide new insight into mechanisms that upregulate ST6Gal-I expression in ovarian cancer cells, and also point to the possibility that some of the CSC characteristics commonly attributed to Sox2 may, in part, be mediated through the sialyltransferase activity of ST6Gal-I.http://link.springer.com/article/10.1186/s13048-019-0574-5Sialic acidST6Gal-ISox23q26 ampliconCancer stem cellsOvarian cancer |
| spellingShingle | Kaitlyn A. Dorsett Robert B. Jones Katherine E. Ankenbauer Anita B. Hjelmeland Susan L. Bellis Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells Journal of Ovarian Research Sialic acid ST6Gal-I Sox2 3q26 amplicon Cancer stem cells Ovarian cancer |
| title | Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells |
| title_full | Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells |
| title_fullStr | Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells |
| title_full_unstemmed | Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells |
| title_short | Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells |
| title_sort | sox2 promotes expression of the st6gal i glycosyltransferase in ovarian cancer cells |
| topic | Sialic acid ST6Gal-I Sox2 3q26 amplicon Cancer stem cells Ovarian cancer |
| url | http://link.springer.com/article/10.1186/s13048-019-0574-5 |
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