Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.
Psychiatry Department, Shanxi Bethune Hospital, Taiyuan, Shanxi, 030000, China.
Cell Death Differ. 2022 Sep;29(9):1850-1863. doi: 10.1038/s41418-022-00970-9. Epub 2022 Mar 25.
Ferroptosis, a novel form of regulated cell death induced by iron-dependent lipid peroxidation, plays an essential role in the development and drug resistance of tumors. Long noncoding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be involved in the regulation of cell cycle, proliferation, apoptosis, and migration of tumor cells. However, the function and molecular mechanism of NEAT1 in regulating ferroptosis in tumors remain unclear. Here, we found that ferroptosis inducers erastin and RSL3 increased NEAT1 expression by promoting the binding of p53 to the NEAT1 promoter. Induced NEAT1 promoted the expression of MIOX by competitively binding to miR-362-3p. MIOX increased ROS production and decreased the intracellular levels of NADPH and GSH, resulting in enhanced erastin- and RSL3-induced ferroptosis. Importantly, overexpression of NEAT1 increased the anti-tumor activity of erastin and RSL3 by enhancing ferroptosis both in vitro and in vivo. Collectively, these data suggest that NEAT1 plays a novel and indispensable role in ferroptosis by regulating miR-362-3p and MIOX. Considering the clinical findings that HCC patients are insensitive to chemotherapy and immunotherapy, ferroptosis induction may be a promising therapeutic strategy for HCC patients with high NEAT1 expression.
铁死亡是一种由铁依赖性脂质过氧化诱导的新型细胞程序性死亡方式，在肿瘤的发生发展和耐药性中发挥着重要作用。长链非编码 RNA（lncRNA）核斑组装转录本 1（NEAT1）已被报道参与肿瘤细胞的细胞周期、增殖、凋亡和迁移的调控。然而，NEAT1 在调节肿瘤中铁死亡的功能和分子机制尚不清楚。在这里，我们发现铁死亡诱导剂 erastin 和 RSL3 通过促进 p53 与 NEAT1 启动子的结合来增加 NEAT1 的表达。诱导的 NEAT1 通过竞争性结合 miR-362-3p 来促进 MIOX 的表达。MIOX 增加 ROS 产生并降低细胞内 NADPH 和 GSH 的水平，导致增强的 erastin 和 RSL3 诱导的铁死亡。重要的是，NEAT1 的过表达通过增强铁死亡增强了 erastin 和 RSL3 在体外和体内的抗肿瘤活性。总之，这些数据表明，NEAT1 通过调节 miR-362-3p 和 MIOX 在铁死亡中发挥新的和不可或缺的作用。鉴于 HCC 患者对化疗和免疫治疗不敏感的临床发现，铁死亡诱导可能是一种有前途的治疗策略，适用于高 NEAT1 表达的 HCC 患者。
