Delta-catenin is required for cell proliferation in virus-positive Merkel cell carcinoma cell lines but not in human fibroblasts
ABSTRACT Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer often driven by the integration of Merkel cell polyomavirus (MCPyV) into the host genome and the persistent expression of its viral oncoproteins, small tumor (ST) antigen, and truncated large tumor (t-LT) antigen....
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American Society for Microbiology
2025-06-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00832-25 |
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| author | Joselyn Landazuri Vinueza Nicholas J. H. Salisbury Kristine N. Dye Ann Roman Denise A. Galloway |
| author_facet | Joselyn Landazuri Vinueza Nicholas J. H. Salisbury Kristine N. Dye Ann Roman Denise A. Galloway |
| author_sort | Joselyn Landazuri Vinueza |
| collection | DOAJ |
| description | ABSTRACT Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer often driven by the integration of Merkel cell polyomavirus (MCPyV) into the host genome and the persistent expression of its viral oncoproteins, small tumor (ST) antigen, and truncated large tumor (t-LT) antigen. While human fibroblasts support MCPyV replication, the cell of origin for MCC remains unknown. We hypothesized that MCPyV initially replicates in fibroblasts but, in rare cases, infects Merkel cell progenitors, contributing to MCC development. Using TurboID mass spectrometry, we identified δ-catenin as a novel ST interactor in fibroblasts. However, while ST binds δ-catenin in fibroblasts, this interaction is absent in virus-positive (VP)-MCC cell lines. Despite this, δ-catenin is essential for VP-MCC, but not for fibroblast cell proliferation. We found that fibroblasts predominantly express δ-catenin isoform 1, whereas VP-MCC cells mainly express isoform 3. Overexpression of isoform 1 in VP-MCC failed to restore ST binding. δ-Catenin promotes VP-MCC proliferation by regulating cell cycle gene expression through its interaction with Kaiso, a transcriptional repressor. Additionally, we found that lysine-specific histone demethylase 1 (LSD1, also known as KDM1A) regulates δ-catenin isoform 3 expression by modulating ESRP1, a δ-catenin splicing factor. Our findings reveal novel host factors involved in MCPyV infection and MCC tumorigenesis, suggesting that the host cell supporting viral replication and the MCC cell of origin may be distinct cell types.IMPORTANCEMerkel cell polyomavirus (MCPyV), the only known human oncogenic polyomavirus, is the primary cause of Merkel cell carcinoma (MCC), a rare and aggressive type of skin cancer. MCC is driven by two viral proteins: small T (ST) and large T (LT). While the virus can replicate in skin fibroblasts, it is still unknown which type of skin cell becomes cancerous. We found that ST binds to a host protein, δ-catenin in fibroblasts, potentially playing a role in the virus lifecycle, but this interaction is missing in the cancer cells. Our study provides evidence that the cells in which the virus replicates and causes cancer are different. |
| format | Article |
| id | doaj-art-6a6f932c948f4c4ea60e99eae2ffb0eb |
| institution | DOAJ |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-6a6f932c948f4c4ea60e99eae2ffb0eb2025-08-20T03:10:50ZengAmerican Society for MicrobiologymBio2150-75112025-06-0116610.1128/mbio.00832-25Delta-catenin is required for cell proliferation in virus-positive Merkel cell carcinoma cell lines but not in human fibroblastsJoselyn Landazuri Vinueza0Nicholas J. H. Salisbury1Kristine N. Dye2Ann Roman3Denise A. Galloway4Department of Microbiology, University of Washington, Seattle, Washington, USAHuman Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USADepartment of Global Health, University of Washington, Seattle, Washington, USADepartment of Microbiology, University of Washington, Seattle, Washington, USADepartment of Microbiology, University of Washington, Seattle, Washington, USAABSTRACT Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer often driven by the integration of Merkel cell polyomavirus (MCPyV) into the host genome and the persistent expression of its viral oncoproteins, small tumor (ST) antigen, and truncated large tumor (t-LT) antigen. While human fibroblasts support MCPyV replication, the cell of origin for MCC remains unknown. We hypothesized that MCPyV initially replicates in fibroblasts but, in rare cases, infects Merkel cell progenitors, contributing to MCC development. Using TurboID mass spectrometry, we identified δ-catenin as a novel ST interactor in fibroblasts. However, while ST binds δ-catenin in fibroblasts, this interaction is absent in virus-positive (VP)-MCC cell lines. Despite this, δ-catenin is essential for VP-MCC, but not for fibroblast cell proliferation. We found that fibroblasts predominantly express δ-catenin isoform 1, whereas VP-MCC cells mainly express isoform 3. Overexpression of isoform 1 in VP-MCC failed to restore ST binding. δ-Catenin promotes VP-MCC proliferation by regulating cell cycle gene expression through its interaction with Kaiso, a transcriptional repressor. Additionally, we found that lysine-specific histone demethylase 1 (LSD1, also known as KDM1A) regulates δ-catenin isoform 3 expression by modulating ESRP1, a δ-catenin splicing factor. Our findings reveal novel host factors involved in MCPyV infection and MCC tumorigenesis, suggesting that the host cell supporting viral replication and the MCC cell of origin may be distinct cell types.IMPORTANCEMerkel cell polyomavirus (MCPyV), the only known human oncogenic polyomavirus, is the primary cause of Merkel cell carcinoma (MCC), a rare and aggressive type of skin cancer. MCC is driven by two viral proteins: small T (ST) and large T (LT). While the virus can replicate in skin fibroblasts, it is still unknown which type of skin cell becomes cancerous. We found that ST binds to a host protein, δ-catenin in fibroblasts, potentially playing a role in the virus lifecycle, but this interaction is missing in the cancer cells. Our study provides evidence that the cells in which the virus replicates and causes cancer are different.https://journals.asm.org/doi/10.1128/mbio.00832-25Merkel cell carcinomaMerkel cell polyomavirusδ-catenin |
| spellingShingle | Joselyn Landazuri Vinueza Nicholas J. H. Salisbury Kristine N. Dye Ann Roman Denise A. Galloway Delta-catenin is required for cell proliferation in virus-positive Merkel cell carcinoma cell lines but not in human fibroblasts mBio Merkel cell carcinoma Merkel cell polyomavirus δ-catenin |
| title | Delta-catenin is required for cell proliferation in virus-positive Merkel cell carcinoma cell lines but not in human fibroblasts |
| title_full | Delta-catenin is required for cell proliferation in virus-positive Merkel cell carcinoma cell lines but not in human fibroblasts |
| title_fullStr | Delta-catenin is required for cell proliferation in virus-positive Merkel cell carcinoma cell lines but not in human fibroblasts |
| title_full_unstemmed | Delta-catenin is required for cell proliferation in virus-positive Merkel cell carcinoma cell lines but not in human fibroblasts |
| title_short | Delta-catenin is required for cell proliferation in virus-positive Merkel cell carcinoma cell lines but not in human fibroblasts |
| title_sort | delta catenin is required for cell proliferation in virus positive merkel cell carcinoma cell lines but not in human fibroblasts |
| topic | Merkel cell carcinoma Merkel cell polyomavirus δ-catenin |
| url | https://journals.asm.org/doi/10.1128/mbio.00832-25 |
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