LncRNA SOX2OT promotes temozolomide resistance by elevating SOX2 expression via ALKBH5-mediated epigenetic regulation in glioblastoma

Abstract

Temozolomide (TMZ) resistance is a major cause of recurrence and poor prognosis in glioblastoma (GBM). Recently, increasing evidences suggested that long noncoding RNAs (LncRNAs) modulate GBM biological processes, especially in resistance to chemotherapy, but their role in TMZ chemoresistance has not been fully illuminated. Here, we found that LncRNA SOX2OT was increased in TMZ-resistant cells and recurrent GBM patient samples, and abnormal expression was correlated with high risk of relapse and poor prognosis. Knockdown of SOX2OT suppressed cell proliferation, facilitated cell apoptosis, and enhanced TMZ sensitivity. In addition, we identified that SOX2OT regulated TMZ sensitivity by increasing SOX2 expression and further activating the Wnt5a/β-catenin signaling pathway in vitro and in vivo. Mechanistically, further investigation revealed that SOX2OT recruited ALKBH5, which binds with SOX2, demethylating the SOX2 transcript, leading to enhanced SOX2 expression. Together, these results demonstrated that LncRNA SOX2OT inhibited cell apoptosis, promoted cell proliferation, and TMZ resistance by upregulating SOX2 expression, which activated the Wnt5a/β-catenin signaling pathway. Our findings indicate that LncRNA SOX2OT may serve as a novel biomarker for GBM prognosis and act as a therapeutic target for TMZ treatment.

LncRNA SOX2‐OT regulates AKT/ERK and SOX2/GLI‐1 expression, hinders therapy, and worsens clinical prognosis in malignant lung diseases

“…The MTA3/SOX2-OT/SOX2 axis has been involved as a prognostic factor for poor clinical outcomes in esophageal squamous cell carcinoma patients [40]. Results from our study confirm that overexpressed LncRNA SOX2-OT is involved in the control of SOX2-OT/SOX2/GLI-1 axis expression, as probable key archetypes, including as "scaffold" to RNA-binding protein (RBP) [65], and ceRNA function reported on SOX2-targeting miR200c [15], or hypothetically involved in ceRNA activity on miR326 [66], or miR218 [67] whose miRNAs are involved in GLI-1targeting. Some of these functional archetypes have been shown or suggested to participate in therapy resistance and clinical prognosis in lung cancer, as it has been previously reported [68].…”

Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities

“…Furthermore, the mechanism of balance between canonical and noncanonical Wnt signaling should be addressed. For example, Wnt5a antagonizes canonical Wnt/β-Catenin signaling and exhibits tumor-suppressive activity in some circumstances [ 221 , 481 – 483 ], but other studies have reported that Wnt5a controls both canonical and noncanonical Wnt signaling [ 15 , 16 , 484 ]. Nusse et al explained that Wnt5a activates or inhibits β-Catenin–TCF signaling depending on the receptor context [ 485 ].…”

The m6A RNA Demethylase ALKBH5 Promotes Radioresistance and Invasion Capability of Glioma Stem Cells

“…In this study, ALKBH5 contributed to GBMSC maintenance, proliferation, and tumorigenicity by enhancing the expression of the transcription factor FOXM1 [ 14 ]. Recently, the role of ALKBH5 has been confirmed in the proliferation of GBM cell lines via the upregulation of SOX2 expression [ 15 ].…”