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Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de‐palmitoylation

索拉非尼 基因敲除 癌症研究 细胞凋亡 肝细胞癌 化学 生物 生物化学
作者
Zhehao Shi,Zhiming Li,Bin Jin,Wen Ye,Luhui Wang,Sina Zhang,Jiuyi Zheng,Zixia Lin,Bo Chen,Fangting Liu,Baofu Zhang,Xiwei Ding,Zhen Yang,Yunfeng Shan,Zhengping Yu,Yi Wang,Jicai Chen,Qiang Chen,Lewis R. Roberts,Gang Chen
出处
期刊:Clinical and translational medicine [Wiley]
卷期号:13 (6) 被引量:22
标识
DOI:10.1002/ctm2.1300
摘要

Abstract Background Ferroptosis is an important iron‐dependent form of cell death in hepatocellular carcinoma (HCC). Sorafenib, a potent ferroptosis inducer, is used to treat advanced HCC but its efficacy is limited by the development of drug resistance. Methods The effects of DUXAP8 expression on HCC progression were evaluated by TCGA database, Kaplan‐Meier analysis, and in situ hybridization analysis. Sorafenib resistant HCC cell lines were modeled in vitro to study the regulation of DUXAP8 on ferroptosis in HCC induced by sorafenib. We used RNA pull‐down, immunofluorescence assays, acyl‐biotinyl exchange assay and mass spectrometry analysis to assess the molecular mechanism of ferroptosis regulation by DUXAP8. Syngeneic subcutaneous and orthotopic CDX models were used to assess whether DUXAP8 inhibition improves HCC in vivo. Results LncRNA DUXAP8, which is highly expressed in liver cancer and associated with poor prognosis, contributes to sorafenib resistance through suppression of ferroptosis. In vitro tests revealed that DUXAP8 reduced the sensitivity of HCC to sorafenib‐induced ferroptosis by acting on SLC7A11, a subunit of the amino acid antiporter system xc‐. DUXAP8 facilitates SLC7A11 palmitoylation and impedes its lysosomal degradation, thereby enhancing SLC7A11 action and suppressing ferroptosis. RNA pull‐down and immunofluorescence assays confirmed that DUXAP8 decreased membrane translocation and promoted sorting of de‐palmitoylated SLC7A11 to lysosomes by binding of DUXAP8 to SLC7A11. In addition, mass spectrometric analysis found that the Cys414 residue of SLC7A11 might be the predominant mutant site responsible for molecular masking of SLC7A11 lysosomal sorting. Further, the antitumor effect of DUXAP8 knockdown was verified in orthotopic and subcutaneous CDX models. Conclusions Our findings suggest that a novel translational strategy combining sorafenib with DUXAP8 silencing to overcome drug resistance may improve treatment efficacy in patients with advanced HCC.
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