2. Academic Validation
  3. Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de-palmitoylation

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

  • Clin Transl Med. 2023 Jun;13(6):e1300. doi: 10.1002/ctm2.1300.
Zhehao Shi 1 2,  Zhiming Li 1,  Bin Jin 3 4,  Wen Ye 5,  Luhui Wang 2,  Sina Zhang 2,  Jiuyi Zheng 2,  Zixia Lin 2,  Bo Chen 2,  Fangting Liu 2,  Baofu Zhang 2,  Xiwei Ding 6,  Zhen Yang 7,  Yunfeng Shan 2 8,  Zhengping Yu 2 8,  Yi Wang 9,  Jicai Chen 10,  Qiang Chen 11 12,  Lewis R Roberts 13,  Gang Chen 2 8
Affiliations

Affiliations

  • 1 Department of Dermatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 2 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3 Department of Organ Transplantation, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong, China.
  • 4 Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Shandong, China.
  • 5 Department of Breast Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
  • 6 Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
  • 7 Department of Infectious Diseases, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.
  • 8 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 9 Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.
  • 10 Department of Hernia and Abdominal Wall Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 11 Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, Arkansas, China.
  • 12 MOE Frontier Science Centre for Precision Oncology, University of Macau, Taipa, Macau, Arkansas, China.
  • 13 Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.
PMID: 37337470 DOI: 10.1002/ctm2.1300
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.

Keywords

DUXAP8; ferroptosis; hepatocellular carcinoma; sorafenib resistance.

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