PTBP1 modulates osteosarcoma chemoresistance to cisplatin by regulating the expression of the copper transporter SLC31A1

Abstract

Abstract Chemoresistance is the main obstacle of treatment in patients with osteosarcoma. RNA‐binding protein PTBP1 has been identified as an oncogene in various cancers. However, the role of PTBP1 in osteosarcoma, especially in chemoresistant osteosarcoma, and the underlying mechanism remain unclear. In this study, we aimed to explore the functions of PTBP1 in chemoresistance of osteosarcoma. We found that PTBP1 was significantly increased in chemotherapeutically insensitive osteosarcoma tissues and cisplatin‐resistant osteosarcoma cell lines (MG‐63 CISR and U‐2OS CISR ) as compared to chemotherapy‐sensitive osteosarcoma tissues and cell lines. Knock‐down of PTBP1 can enhance the anti‐proliferation and apoptosis‐induced effects of cisplatin in MG‐63 CISR and U‐2OS CISR cells. Moreover, PTBP1 knock‐down significantly up‐regulated the expression of the copper transporter SLC31A1, as indicated by transcriptome sequencing. Through RNA immunoprecipitation, dual‐luciferase reporter assay and RNA stability detection, we confirmed that PTBP1 binds to SLC31A1 mRNA and regulates the expression level of SLC31A1 by affecting mRNA stability. Additionally, SLC31A1 silencing abrogated the chemosensitizing effect of PTBP1 knock‐down in MG‐63 CISR and U‐2OS CISR cells. Using a nude mouse xenograft model, we further confirmed that PTBP1 knock‐down enhanced chemoresistant osteosarcoma responsiveness to cisplatin treatment in vivo. Collectively, the present study suggests that PTBP1 is a crucial determinant of chemoresistance in osteosarcoma.