Viral Status Predicts the Patterns of Genome Methylation and Decitabine Response in Merkel Cell Carcinoma
| Autor: | Monique Verhaegen, Arul M. Chinnaiyan, Julia VanGoor, Drew Pratt, Doris Mangelberger, Xuhong Cao, Fengyun Su, Andrzej A. Dlugosz, Jean C. Tien, Josh N. Vo, Jae Eun Choi, Paul W. Harms, Vincent T. Ma, Saravana M. Dhanasekaran |
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| Rok vydání: | 2022 |
| Předmět: |
Skin Neoplasms
Merkel cell polyomavirus Decitabine Dermatology Biochemistry Article Mice medicine Animals Humans Epigenetics Molecular Biology Polyomavirus Infections biology Merkel cell carcinoma food and beverages Cell Biology Methylation DNA Methylation biology.organism_classification medicine.disease Carcinoma Merkel Cell Tumor Virus Infections medicine.anatomical_structure Hypomethylating agent DNA methylation Cancer research Merkel cell medicine.drug |
| Zdroj: | J Invest Dermatol |
| ISSN: | 0022-202X |
| Popis: | Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that is classified as Merkel cell polyomavirus (MCPyV)-positive or virus-negative. Epigenetic changes, such as DNA methylation, can alter gene expression and influence cancer progression. However, patterns of DNA methylation and the therapeutic efficacy of hypomethylating agents have not been fully explored in MCC. We characterized genome-wide DNA methylation in 16 MCC cell lines from both molecular subclasses in comparison to other cancer types, and found that the overall profile of MCC is similar to small cell lung carcinoma. Comparison of virus-positive and -negative MCC revealed 2,260 differentially methylated positions. The hypomethylating agent decitabine (DAC) upregulated expression of antigen-presenting machinery in MCC cell lines and stimulated membrane expression of HLA-A in virus-positive and virus-negative MCC xenograft tumors. DAC also induced prominent caspase- and large T antigen-independent cell death in virus-positive MCC, whereas virus-negative MCC cell lines displayed decreased proliferation without increased cell death. In mouse xenografts, decitabine significantly decreased the size of virus-positive tumors, but not virus-negative tumors. Our findings indicate that viral status predicts genomic methylation patterns in MCC, and that DAC may be therapeutically effective against MCC via anti-proliferative effects, cell death, and increased immune recognition. |
| Databáze: | OpenAIRE |
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