CREB-induced LINC00473 promotes chemoresistance to TMZ in glioblastoma by regulating O6-methylguanine-DNA-methyltransferase expression via CEBPα binding

Abstract

Temozolomide (TMZ) offers substantial therapeutic benefits for glioblastoma (GB), yet its efficacy is hindered the development of chemoresistance. The role of long non-coding RNAs (lncRNAs) in tumorigenesis and chemoresistance has garnered great attention in studies on TMZ resistance. This study aimed to reveal the role of LINC00473 in TMZ chemoresistance and the underlying mechanism in GB. The expression of LINC00473 in TMZ-resistant and TMZ-sensitive GB cells was investigated using qPCR analysis. The role of LINC00473 in regulating TMZ resistance in GB cells was analyzed using the CCK-8 assay, colony formation assay, and flow cytometry. The next steps included assessing if LINC00473 is regulated by CREB and whether LINC00473 promotes chemoresistance through MGMT regulation via CEBPα. Further, chemoresistance delivery between cells via exosomal LINC00473 was validated in vitro and in vivo. Results showed that LINC00473 levels were elevated in TMZ-resistant cells upon CREB activation, and the lncRNA promoted the chemoresistance of GB cells through the upregulation of MGMT expression. Mechanistically, LINC00473 regulated the MGMT expression by binding to CEBPα. The highly-expressed LINC00473 packaged in exosomes transferred chemoresistance to the adjacent TMZ-sensitive GB cells. In conclusion, a novel CREB/LINC00473/CEBPα/MGMT pathway was revealed in the GB TMZ-resistance formation. In addition, an exosome-based mechanism of chemoresistance transmission was revealed, suggesting that LINC00473 could be used as a novel therapeutic target for GB.