Title

The Role of FAS Receptor Methylation in Osteosarcoma Metastasis.

Document Type

Article

Publication Date

7-29-2023

Keywords

JGM, Mice, Animals, fas Receptor, Bone Neoplasms, Osteosarcoma, Azacitidine, DNA Methylation, CpG Islands, Cell Line, Tumor

JAX Source

Int J Mol Sci. 2023;24(15).

ISSN

1422-0067

PMID

37569529

DOI

https://doi.org/10.3390/ijms241512155

Grant

This work was supported by the Training Program in Biomedical Informatics, National Library of Medicine (T15LM007093), National Cancer Institute (NCI) Therapeutically Applicable Research to Generate Effective Treatments Osteosarcoma (CA98543-07S6), and the Cancer Prevention and Research Institute of Texas (CPRIT) MIRA (RP101335).

Abstract

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.

Comments

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Please contact the Joan Staats Library for information regarding this document.

Share

COinS