RBM15-mediated the m6A modification of MAT2A promotes osteosarcoma cell proliferation, metastasis and suppresses ferroptosis.

Abstract

Methionine adenosyltransferase 2A (MAT2A) has been found to mediate osteosarcoma (OS) progression. Therefore, more roles and mechanisms of MAT2A in the development of OS deserve further exploration. The mRNA and protein levels of MAT2A and RNA binding motif protein 15 (RBM15) were tested by quantitative real-time PCR and western blot (WB). Cell proliferation and metastasis were examined using EdU assay and transwell assay. The protein levels of metastasis-related markers and ferroptosis-related marker were measured by WB. Cell ferroptosis was assessed via testing GSH, ROS, and Fe2+levels. Mice xenograft model was constructed to explore the roles of MAT2A and RBM15 in vivo. RBM15 and MAT2A interaction was assessed by MeRIP assay and dual-luciferase reporter assay. High expression of MAT2A was observed in OS tumor tissues and cells. MAT2A knockdown reduced OS cell proliferation, migration, invasion and enhanced ferroptosis. Silencing of MAT2A inhibited OS tumor growth in vivo. RBM15 was upregulated in OS tumor tissues and cells, which could promote MAT2A expression by N6-methyladenosine (m6A) modification. Downregulation of RBM15 repressed OS cell behaviors and tumorigenesis by decreasing MAT2A expression. In conclusion, MAT2A, regulated by RBM15-mediated m6A modification, accelerated OS malignant progression by increasing cell proliferation, metastasis and decreasing ferroptosis.