Long noncoding RNA just proximal to X-inactive specific transcript facilitates aerobic glycolysis and temozolomide chemoresistance by promoting stability of PDK1 mRNA in an m6A-dependent manner in glioblastoma multiforme cells

Improving the chemotherapy resistance of temozolomide (TMZ) is of great significance in the treatment of glioblastoma multiforme (GBM). Long non-coding RNA just proximal to the X-inactive specific transcript (JPX) has been proven to be involved in cancer progression. However, the intrinsic significance and molecular mechanism by which JPX orchestrates GBM progression and TMZ chemotherapy resistance remain poorly understood. Here, JPX was found to be significantly elevated in GBM tissues and cell lines, and patients with high expressions of JPX showed significantly worse prognoses. Functional experiments revealed its carcinogenic roles in GBM cell proliferation, TMZ chemoresistance, anti-apoptosis, DNA damage repair, and aerobic glycolysis. Mechanistically, JPX formed a complex with phosphoinositide dependent kinase-1 (PDK1) messenger RNA (mRNA) and promoted its stability and expression. Furthermore, an RNA immunoprecipitation (RIP) experiment showed that JPX interacted with N6-methyladenosine (m6A) demethylase FTO alpha-ketoglutarate dependent dioxygenase (FTO) and enhanced FTO-mediated PDK1 mRNA demethylation. JPX exerted its GBM-promotion effects through the FTO/PDK1 axis. Taken together, these findings reveal the key role of JPX in promoting GBM aerobic glycolysis and TMZ chemoresistance in an m6A-dependent manner. Thus, it comprises a promising novel therapeutic target for GBM chemotherapy.

Automated summary

The study demonstrates that JPX promotes GBM progression and TMZ chemoresistance through the FTO/PDK1 axis, revealing its key role in GBM aerobic glycolysis in an m6A-dependent manner. These findings suggest that JPX could be a potential therapeutic target for GBM chemotherapy.