Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation
Abstract Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancie...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45324-w |
| _version_ | 1797274008778964992 |
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| author | Qian Liu Emma Adhikari Daniel K. Lester Bin Fang Joseph O. Johnson Yijun Tian Andrea T. Mockabee-Macias Victoria Izumi Kelly M. Guzman Michael G. White John M. Koomen Jennifer A. Wargo Jane L. Messina Jianfei Qi Eric K. Lau |
| author_facet | Qian Liu Emma Adhikari Daniel K. Lester Bin Fang Joseph O. Johnson Yijun Tian Andrea T. Mockabee-Macias Victoria Izumi Kelly M. Guzman Michael G. White John M. Koomen Jennifer A. Wargo Jane L. Messina Jianfei Qi Eric K. Lau |
| author_sort | Qian Liu |
| collection | DOAJ |
| description | Abstract Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancies are poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). Global phosphoproteomic and fucoproteomic profiling, coupled with in vitro and in vivo functional validation, further reveal that AR-induced FUT4 fucosylates L1 cell adhesion molecule (L1CAM), which is required for FUT4-increased metastatic capacity. Tumor microarray and gene expression analyses demonstrate that AR-FUT4-L1CAM-AJs signaling correlates with pathological staging in melanoma patients. By delineating key androgen-triggered signaling that enhances metastatic aggressiveness, our findings help explain sex-associated clinical outcome disparities and highlight AR/FUT4 and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma. |
| first_indexed | 2024-03-07T14:52:15Z |
| format | Article |
| id | doaj.art-1d6b5538888248d5b44646f3fe07e1be |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:52:15Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-1d6b5538888248d5b44646f3fe07e1be2024-03-05T19:37:47ZengNature PortfolioNature Communications2041-17232024-02-0115112010.1038/s41467-024-45324-wAndrogen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylationQian Liu0Emma Adhikari1Daniel K. Lester2Bin Fang3Joseph O. Johnson4Yijun Tian5Andrea T. Mockabee-Macias6Victoria Izumi7Kelly M. Guzman8Michael G. White9John M. Koomen10Jennifer A. Wargo11Jane L. Messina12Jianfei Qi13Eric K. Lau14Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research InstituteDepartment of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research InstituteDepartment of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research InstituteProteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research InstituteAnalytic Microscopy Core, H. Lee Moffitt Cancer Center & Research InstituteDepartment of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research InstituteDepartment of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research InstituteProteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research InstituteAnalytic Microscopy Core, H. Lee Moffitt Cancer Center & Research InstituteDepartment of Surgical Oncology, MD Anderson Cancer CenterProteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research InstituteDepartment of Surgical Oncology, MD Anderson Cancer CenterDepartment of Pathology, H. Lee Moffitt Cancer Center & Research InstituteDepartment of Biochemistry and Molecular Biology, University of Maryland School of MedicineDepartment of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research InstituteAbstract Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancies are poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). Global phosphoproteomic and fucoproteomic profiling, coupled with in vitro and in vivo functional validation, further reveal that AR-induced FUT4 fucosylates L1 cell adhesion molecule (L1CAM), which is required for FUT4-increased metastatic capacity. Tumor microarray and gene expression analyses demonstrate that AR-FUT4-L1CAM-AJs signaling correlates with pathological staging in melanoma patients. By delineating key androgen-triggered signaling that enhances metastatic aggressiveness, our findings help explain sex-associated clinical outcome disparities and highlight AR/FUT4 and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma.https://doi.org/10.1038/s41467-024-45324-w |
| spellingShingle | Qian Liu Emma Adhikari Daniel K. Lester Bin Fang Joseph O. Johnson Yijun Tian Andrea T. Mockabee-Macias Victoria Izumi Kelly M. Guzman Michael G. White John M. Koomen Jennifer A. Wargo Jane L. Messina Jianfei Qi Eric K. Lau Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation Nature Communications |
| title | Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation |
| title_full | Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation |
| title_fullStr | Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation |
| title_full_unstemmed | Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation |
| title_short | Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation |
| title_sort | androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation |
| url | https://doi.org/10.1038/s41467-024-45324-w |
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