Circular RNA cIARS regulates ferroptosis in HCC cells through interacting with RNA binding protein ALKBH5

Zhiqian Liu; Qi Wang; Xin Wang; Zongzhen Xu; Xiaoqing Wei; Jie Li

doi:10.1038/s41420-020-00306-x

Circular RNA cIARS regulates ferroptosis in HCC cells through interacting with RNA binding protein ALKBH5

Cell Death Discov. 2020 Aug 7:6:72. doi: 10.1038/s41420-020-00306-x. eCollection 2020.

Authors

Zhiqian Liu^#^{1

2}, Qi Wang^#², Xin Wang¹, Zongzhen Xu¹, Xiaoqing Wei³, Jie Li^{1

2}

Affiliations

¹ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Shandong First Medical University, 250014 Jinan, Shandong China.
² Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, 250014 Jinan, Shandong China.
³ Department of Reproduction Medicine, Jinan Maternal and Child Health Care Hospital Affiliated to Shandong First Medical University, 250001 Jinan, Shandong China.

^# Contributed equally.

Abstract

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.

Keywords: Autophagy; Cell death; Targeted therapies.