Department of Neurosurgery, Wuhan Third Hospital, Tongren Hospital of Wuhan University, 430060, Wuhan, China.
Department of 120 treatment center, Wuhan Third Hospital, Tongren Hospital of Wuhan University, 430060, Wuhan, China.
Metab Brain Dis. 2023 Apr;38(4):1351-1364. doi: 10.1007/s11011-023-01184-9. Epub 2023 Mar 11.
Histone deacetylase (HDAC) inhibitor-based therapeutic drug tolerance is a major obstacle to glioblastoma (GBM) treatment. Meanwhile, non-coding RNAs have been reported to be involved in the regulation of HDAC inhibitor (SAHA) tolerance in some human tumors. However, the relationship between circular RNAs (circRNAs) and SAHA tolerance is still unknown. Herein, we explored the role and mechanism of circ_0000741 on SAHA tolerance in GBM.
Circ_0000741, microRNA-379-5p (miR-379-5p), and tripartite motif-containing 14 (TRIM14) level were detected by real-time quantitative polymerase chain reaction (RT-qPCR). (4-5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), Colony formation, flow cytometry, and transwell assays were used to detect SAHA tolerance, proliferation, apoptosis, and invasion in SAHA-tolerant GBM cells. Western blot analysis of protein levels of E-cadherin, N-cadherin, and TRIM14. After Starbase2.0 analysis, the binding between miR-379-5p and circ_0000741 or TRIM14 was proved using a dual-luciferase reporter. The role of circ_0000741 on drug tolerance was assessed using a xenograft tumor model in vivo.
Circ_0000741 and TRIM14 were upregulated, and miR-379-5p was reduced in SAHA-tolerant GBM cells. Furthermore, circ_0000741 absence reduced SAHA tolerance, suppressed proliferation, invasion, and induced apoptosis in SAHA-tolerant GBM cells. Mechanistically, circ_0000741 might affect TRIM14 content via sponging miR-379-5p. Besides, circ_0000741 silencing enhanced the drug sensitivity of GBM in vivo.
Circ_0000741 might accelerate SAHA tolerance by regulating the miR-379-5p/TRIM14 axis, which provided a promising therapeutic target for GBM treatment.
组蛋白去乙酰化酶（HDAC）抑制剂为基础的治疗药物耐受是胶质母细胞瘤（GBM）治疗的主要障碍。同时，非编码 RNA 已被报道参与一些人类肿瘤中 HDAC 抑制剂（SAHA）耐受的调节。然而，环状 RNA（circRNA）与 SAHA 耐受的关系尚不清楚。在此，我们探讨了 circ_0000741 在 GBM 中对 SAHA 耐受的作用和机制。
实时定量聚合酶链反应（RT-qPCR）检测 circ_0000741、microRNA-379-5p（miR-379-5p）和三肽重复含 14 个（TRIM14）的水平。（4-5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐（MTT）、5-乙炔基-2'-脱氧尿苷（EdU）、集落形成、流式细胞术和 Transwell 分析用于检测 SAHA 耐受、增殖、凋亡和 SAHA 耐受 GBM 细胞的侵袭。Western blot 分析蛋白水平的 E-钙粘蛋白、N-钙粘蛋白和 TRIM14。通过 Starbase2.0 分析，证明了 miR-379-5p 与 circ_0000741 或 TRIM14 的结合是双荧光素酶报告。体内异种移植肿瘤模型评估了 circ_0000741 对药物耐受性的作用。
SAHA 耐受 GBM 细胞中 circ_0000741 和 TRIM14 上调，miR-379-5p 下调。此外，circ_0000741 缺失降低了 SAHA 耐受，抑制了 SAHA 耐受 GBM 细胞的增殖、侵袭，并诱导了凋亡。机制上，circ_0000741 可能通过海绵吸附 miR-379-5p 影响 TRIM14 含量。此外，circ_0000741 沉默增强了 GBM 的体内药物敏感性。
circ_0000741 可能通过调节 miR-379-5p/TRIM14 轴加速 SAHA 耐受，为 GBM 治疗提供了有前途的治疗靶点。
