ABSTRACT
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.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Brain Neoplasms/metabolism , Glioblastoma/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , RNA, Long Noncoding/metabolism , Temozolomide/pharmacology , Adenosine/analogs & derivatives , Adenosine/metabolism , Aerobiosis , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Cell Line, Tumor , Demethylation , Disease Progression , Drug Resistance, Neoplasm , Glioblastoma/drug therapy , Glioblastoma/mortality , Glioblastoma/pathology , Glycolysis , Humans , Neoplasm Proteins/metabolism , Prognosis , RNA, Messenger/metabolismABSTRACT
OBJECTIVES: To evaluate the expression of TAZ and its role in tumor invasion and metastasis in human glioma. METHODS: The expression of TAZ protein was measured in 48 samples of surgically resected human glioma and 13 samples of normal brain tissues using immunohistochemistry. TAZ was knocked down by a retrovirus-mediated TAZ shRNA in a glioma cell line, SNB19. Transwell cell migration and invasion assays were used to determine migration and invasion of SNB19 cells. RESULTS: The positive expression rate of TAZ protein in glioma tissues was significantly higher than that in normal brain tissues (79.2% vs. 15.4%, P<0.001). Furthermore, clinical analysis suggested that the positive expression rate of TAZ protein in poorly differentiated tumor tissues was significantly higher as compared with that in well differentiated tissues (96.0% vs. 60.9%, P<0.01). TAZ was significantly knocked down by TAZ shRNA (P<0.001), and TAZ knockdown significantly reduced cell migration and invasion (P<0.01, respectively) in SNB19 cells. CONCLUSIONS: TAZ protein overexpression is observed in human glioma and its elevated expression is significantly correlated with poor differentiation. TAZ knockdown prominently reduces cell migration and invasion in SNB19 cells, suggesting that TAZ may play a key role in the initiation and progression of human glioma.
