LncRNA-mediated TPI1 and PKM2 promote self-renewal and chemoresistance in GBM

Abstract

AbstractBackground Temozolomide (TMZ) resistance is one of the major reasons for the poor prognosis of glioblastoma patients. Long noncoding RNAs (lncRNAs) are widely involved in multiple biological processes, including TMZ resistance. We previously showed that Linc00942 is a potential regulator of TMZ sensitivity in glioblastoma (GBM) cells. However, the underlying mechanism of TMZ resistance induced by Linc00942 is unknown. Methods We performed a rapid amplification of cDNA ends (RACE) assay in TMZ-resistant GBM cells to confirm the sequence of Linc00942. ChIRP-MS and ChIRP-WB assays showed that Linc00492 interacted with TPI1 and PKM2. Molecular docking analysis, RNA pull-down, and RIP assays were used to demonstrate the underlying mechanisms of Linc00942 binding with TPI1 and PKM2. Native PAGE was used to identify the polymers of TPI1 and PKM2. The efficiency of Linc00942-mediated TMZ resistance was detected in vitro and in vivo. Results In this study, we identified the sequence of Linc00942, and further experiments confirmed that Linc00942 contributes to self-renewal and TMZ resistance in GBM cells. Linc00942 interacts with TPI1 and PKM2, subsequently promoting the phosphorylation, dimerization, and nuclear translocation of both proteins. The interaction of Linc00942 with TPI1 and PKM2 leads to increased acetylation of H3K4 and activation of the STAT3/P300 axis, resulting in the marked transcriptional activation of SOX9. Moreover, knockdown of SOX9 reversed the TMZ resistance induced by Linc00492 both in vitro and in vivo. Conclusions Linc00942 strongly promotes SOX9 by interacting with TPI1 and PKM2, thereby driving self-renewal and TMZ resistance in GBM cells. These findings provide potential combined therapeutic strategies to overcome TMZ resistance in GBM.