High expression of LncRNA HOTAIR is a risk factor for temozolomide resistance in glioblastoma via activation of the miR-214/β-catenin/MGMT pathway

• Published in: Scientific reports 2024-10, Vol.14 (1), p.26224-13, Article 26224
• Main Authors: Lan, Tian, Quan, Wei, Yu, Dong-Hu, Chen, Xi, Wang, Ze-Fen, Li, Zhi-Qiang
• Format: Article
• Language: English
• Subjects: 631/67/1059; 631/67/1922; 631/67/68; Antineoplastic Agents, Alkylating - pharmacology; Antisense RNA; Antisense therapy; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; beta Catenin - genetics; beta Catenin - metabolism; Bioinformatics; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell cycle; Cell Line, Tumor; Cell lines; Cell viability; Cytotoxicity; DNA Modification Methylases - genetics; DNA Modification Methylases - metabolism; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; Drug Resistance, Neoplasm - genetics; Flow cytometry; Gene Expression Regulation, Neoplastic - drug effects; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioma; Humanities and Social Sciences; Humans; lncRNA HOTAIR; Methotrexate; MicroRNAs - genetics; MicroRNAs - metabolism; multidisciplinary; Resistance; Risk Factors; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Science; Science (multidisciplinary); Temozolomide; Temozolomide - pharmacology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Wnt protein; Wnt Signaling Pathway - drug effects; Wnt Signaling Pathway - genetics; Β-catenin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-77348-z

HOX transcript antisense RNA (HOTAIR) is upregulated in glioblastoma (GBM) and associated with temozolomide (TMZ) resistance. However, the mechanisms underlying HOTAIR-mediated TMZ resistance remains poorly understood. HOTAIR expression in glioma-related public datasets and drug response estimation were analyzed using bioinformatics. These findings were verified by overexpressing HOTAIR in TMZ-sensitive U251 cells and/or silencing HOTAIR in resistant U251 cells (U251R). The cytotoxic effects were evaluated using cell viability assay and flow cytometry analysis of cell cycle and apoptosis. In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/β-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated β-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/β-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and β-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level.