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

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

doi:10.1038/s41420-020-00306-x

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.

Highlights

hepatocellular carcinoma (HCC) is a highly refractory and prevalent cancer worldwide, with ~841,000 new cases and 782,000 deaths every year[1]
We found a novel circRNA derived from the IARS gene (ID from circBase: hsa_circ_0008367), named cIARS. cIARS was proven to be a promoter of ferroptosis in HCC cells after SF treatment, which was partially attributed to the activation of autophagy and ferritinophagy
According to circBase, cIARS is an exonic circRNA ~226 nt in length originating from the exon 13 and exon 14 of the IARS gene on chr9: 95030455–95032265 (Fig. 1c). qPCR showed that the relative expression levels of cIARS were significantly higher in SF-treated cell lines than in untreated ones (Fig. 1d)

Summary

Introduction

HCC is a highly refractory and prevalent cancer worldwide, with ~841,000 new cases and 782,000 deaths every year[1]. Rapid advances in diagnosis and treatment had improved patient outcomes. The survival gains are stage-specific[2]. Transplantation, ablation, or transarterial chemoembolization benefits patients in early or intermediate stages[3], while treatment for late-stage HCC has remained challenging. The standard first-line systemic drug against advanced HCC is sorafenib (SF, BAY 43-9006, Nexavar), which is currently (GSH) was inhibited, resulting in accumulation of lipid peroxidation products, and eventually inducing ferroptosis. When autophagy flux is initially induced, MTORC1 dissociates from the ULK1/2/ATG13 complex, leading to dephosphorylation of the complex[9].

Methods

Results

Conclusion