Circular RNA cIARS regulates ferroptosis in HCC cells through interacting with RNA binding protein ALKBH5
Circular RNA cIARS regulates ferroptosis in HCC cells through interacting with RNA binding protein ALKBH5
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环状 RNA cIARS 通过与 RNA 结合蛋白 ALKBH5 相互作用调节 HCC 细胞的铁死亡
DOI：
10.1038/s41420-020-00306-x
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发表时间：
2020-08-07
影响因子：
7
通讯作者：
Li, Jie
中科院分区：
文献类型：
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作者：
Liu, Zhiqian;Wang, Qi;Li, Jie
环状rna （circRNAs）是一类新颖而独特的非编码rna，由前mrna反向剪接而成。已经证实，circRNAs参与了肝细胞癌（HCC）的多种恶性行为。然而，circRNA在铁下垂调控中的作用及其潜在机制尚不清楚。本研究发现，在索拉非尼（SF）治疗HCC细胞后，cIARS （hsa_circ_0008367）是表达最高的circRNA。抗cIARS的小干扰RNA （si-cIARS）通过灭活铁凋亡显著抑制细胞对SF或Erastin的敏感性，这可能部分归因于抑制自噬和铁蛋白自噬。预测分析和机制鉴定表明，cIARS与RNA结合蛋白（RBP） ALKBH5相互作用，而ALKBH5是HCC自噬通量的负调节因子。由ALKBH5沉默介导的BCL-2/BECN1复合物的解离被si-cIARS有效阻断。此外，ALKBH5下调可显著恢复si-cIARS对铁噬事件、自噬通量和铁蛋白自噬的抑制。综上所述，cIARS可能是一个重要的circRNA，通过抑制alkbh5介导的自噬抑制，积极调节sf诱导的铁细胞凋亡。
Circular RNAs (circRNAs) are a novel and unique class of noncoding RNAs that are back-spliced from pre-mRNAs. It has been confirmed that circRNAs are involved in various malignant behaviors of hepatocellular carcinoma (HCC). However, the role of circRNA in the regulation of ferroptosis and the underlying mechanism remain unknown. Here, cIARS (hsa_circ_0008367) was found to be the most highly expressed circRNA after sorafenib (SF) treatment in HCC cells. Small interfering RNA against cIARS (si-cIARS) significantly suppressed the cellular sensitivity to SF or Erastin through inactivating ferroptosis, which may be partially attributed to the inhibition of autophagy and ferritinophagy. Prediction analysis and mechanistic identification revealed that cIARS physically interacted with RNA binding protein (RBP) ALKBH5, which was a negative regulator of autophagic flux in HCC. The dissociation of BCL-2/BECN1 complex, mediated by ALKBH5 silencing was effectively blocked by si-cIARS. Furthermore, the inhibition of ferroptotic events, autophagic flux and ferritinophagy resulted from si-cIARS, were significantly rescued by ALKBH5 downregulation. Overall, cIARS may be an important circRNA, positively regulating SF-induced ferroptosis through suppressing the ALKBH5-mediated autophagy inhibition.