The Role of FAS Receptor Methylation in Osteosarcoma Metastasis
Osteosarcoma is the most frequent primary malignant bone tumor with an annual incidence of about 400 cases in the United States. Osteosarcoma primarily metastasizes to the lungs, where FAS ligand (FASL) is constitutively expressed. The interaction of FASL and its cell surface receptor, FAS, triggers...
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| Format: | Article |
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MDPI AG
2023-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/15/12155 |
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| author | Jiayi M. Sun Wing-Yuk Chow Gufeng Xu M. John Hicks Manjula Nakka Jianhe Shen Patrick Kwok Shing Ng Aaron M. Taylor Alexander Yu Jason E. Farrar Donald A. Barkauskas Richard Gorlick Jaime M. Guidry Auvil Daniela Gerhard Paul Meltzer Rudy Guerra Tsz-Kwong Man Ching C. Lau on behalf of the TARGET Osteosarcoma Consortium |
| author_facet | Jiayi M. Sun Wing-Yuk Chow Gufeng Xu M. John Hicks Manjula Nakka Jianhe Shen Patrick Kwok Shing Ng Aaron M. Taylor Alexander Yu Jason E. Farrar Donald A. Barkauskas Richard Gorlick Jaime M. Guidry Auvil Daniela Gerhard Paul Meltzer Rudy Guerra Tsz-Kwong Man Ching C. Lau on behalf of the TARGET Osteosarcoma Consortium |
| author_sort | Jiayi M. Sun |
| collection | DOAJ |
| description | Osteosarcoma is the most frequent primary malignant bone tumor with an annual incidence of about 400 cases in the United States. Osteosarcoma primarily metastasizes to the lungs, where FAS ligand (FASL) is constitutively expressed. The interaction of FASL and its cell surface receptor, FAS, triggers apoptosis in normal cells; however, this function is altered in cancer cells. DNA methylation has previously been explored as a mechanism for altering FAS expression, but no variability was identified in the CpG island (CGI) overlapping the promoter. Analysis of an expanded region, including CGI shores and shelves, revealed high variability in the methylation of certain CpG sites that correlated significantly with FAS mRNA expression in a negative manner. Bisulfite sequencing revealed additional CpG sites, which were highly methylated in the metastatic LM7 cell line but unmethylated in its parental non-metastatic SaOS-2 cell line. Treatment with the demethylating agent, 5-azacytidine, resulted in a loss of methylation in CpG sites located within the FAS promoter and restored FAS protein expression in LM7 cells, resulting in reduced migration. Orthotopic implantation of 5-azacytidine treated LM7 cells into severe combined immunodeficient mice led to decreased lung metastases. These results suggest that DNA methylation of CGI shore sites may regulate FAS expression and constitute a potential target for osteosarcoma therapy, utilizing demethylating agents currently approved for the treatment of other cancers. |
| first_indexed | 2024-03-11T00:25:22Z |
| format | Article |
| id | doaj.art-55e97605d05d48298d73d996a1af708f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T00:25:22Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-55e97605d05d48298d73d996a1af708f2023-11-18T23:01:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124151215510.3390/ijms241512155The Role of FAS Receptor Methylation in Osteosarcoma MetastasisJiayi M. Sun0Wing-Yuk Chow1Gufeng Xu2M. John Hicks3Manjula Nakka4Jianhe Shen5Patrick Kwok Shing Ng6Aaron M. Taylor7Alexander Yu8Jason E. Farrar9Donald A. Barkauskas10Richard Gorlick11Jaime M. Guidry Auvil12Daniela Gerhard13Paul Meltzer14Rudy Guerra15Tsz-Kwong Man16Ching C. Lau17on behalf of the TARGET Osteosarcoma ConsortiumProgram of Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatrics-Oncology, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatrics-Oncology, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pathology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatrics-Oncology, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatrics-Oncology, Baylor College of Medicine, Houston, TX 77030, USAThe Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USAProgram of Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatrics-Oncology, Baylor College of Medicine, Houston, TX 77030, USAArkansas Children’s Research Institute and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USADivision of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USAOffice of Cancer Genomics, National Cancer Institute, Bethesda, MD 20892, USAOffice of Cancer Genomics, National Cancer Institute, Bethesda, MD 20892, USAGenetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USADepartment of Statistics, Rice University, Houston, TX 77005, USAProgram of Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USAProgram of Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USAOsteosarcoma is the most frequent primary malignant bone tumor with an annual incidence of about 400 cases in the United States. Osteosarcoma primarily metastasizes to the lungs, where FAS ligand (FASL) is constitutively expressed. The interaction of FASL and its cell surface receptor, FAS, triggers apoptosis in normal cells; however, this function is altered in cancer cells. DNA methylation has previously been explored as a mechanism for altering FAS expression, but no variability was identified in the CpG island (CGI) overlapping the promoter. Analysis of an expanded region, including CGI shores and shelves, revealed high variability in the methylation of certain CpG sites that correlated significantly with FAS mRNA expression in a negative manner. Bisulfite sequencing revealed additional CpG sites, which were highly methylated in the metastatic LM7 cell line but unmethylated in its parental non-metastatic SaOS-2 cell line. Treatment with the demethylating agent, 5-azacytidine, resulted in a loss of methylation in CpG sites located within the FAS promoter and restored FAS protein expression in LM7 cells, resulting in reduced migration. Orthotopic implantation of 5-azacytidine treated LM7 cells into severe combined immunodeficient mice led to decreased lung metastases. These results suggest that DNA methylation of CGI shore sites may regulate FAS expression and constitute a potential target for osteosarcoma therapy, utilizing demethylating agents currently approved for the treatment of other cancers.https://www.mdpi.com/1422-0067/24/15/12155osteosarcomaFAS receptorDNA methylation5-azacytidineprognosis |
| spellingShingle | Jiayi M. Sun Wing-Yuk Chow Gufeng Xu M. John Hicks Manjula Nakka Jianhe Shen Patrick Kwok Shing Ng Aaron M. Taylor Alexander Yu Jason E. Farrar Donald A. Barkauskas Richard Gorlick Jaime M. Guidry Auvil Daniela Gerhard Paul Meltzer Rudy Guerra Tsz-Kwong Man Ching C. Lau on behalf of the TARGET Osteosarcoma Consortium The Role of FAS Receptor Methylation in Osteosarcoma Metastasis International Journal of Molecular Sciences osteosarcoma FAS receptor DNA methylation 5-azacytidine prognosis |
| title | The Role of FAS Receptor Methylation in Osteosarcoma Metastasis |
| title_full | The Role of FAS Receptor Methylation in Osteosarcoma Metastasis |
| title_fullStr | The Role of FAS Receptor Methylation in Osteosarcoma Metastasis |
| title_full_unstemmed | The Role of FAS Receptor Methylation in Osteosarcoma Metastasis |
| title_short | The Role of FAS Receptor Methylation in Osteosarcoma Metastasis |
| title_sort | role of fas receptor methylation in osteosarcoma metastasis |
| topic | osteosarcoma FAS receptor DNA methylation 5-azacytidine prognosis |
| url | https://www.mdpi.com/1422-0067/24/15/12155 |
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