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DLAT as a Cuproptosis Promoter and a Molecular Target of Elesclomol in Hepatocellular Carcinoma

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Abstract

Objective

Cuproptosis is a novel cell death pathway that was newly discovered in early 2022. However, cuproptosis is still in its infancy in many respects and warrants further research in hepatocellular carcinoma (HCC). This study aimed to analyze the mechanism of cuprptosis in HCC.

Methods

Herein, the tumor microenvironment infiltration landscape of molecular subtypes was illustrated using GSVA, ssGSEA, TIMER, CIBERSORT, and ESTIMATE algorithms based on the expression profile of cuproptosis-related genes (CRGs) from TCGA and GEO databases. Then, the least absolute shrinkage and selection operator regression method was applied to construct a cuproptosis signature to quantify the cuproptosis profile of HCC. Further, we explored the expression of three hub CRGs in cell lines and clinical patient tissues of HCC by Western blotting, qRT-PCR and immunohistochemistry. Finally, we examined the function of dihydrolipoamide S-acetyltransferase (DLAT) in cuproptosis in HCC by loss-of-function strategy, Western blotting and CCK8 assay.

Results

Three distinct molecular subtypes were identified. Cluster 2 had the greatest infiltration of immune cells with best prognosis. The cuproptosis signature was indicative of tumor subtype, immunity, and prognosis for HCC, and specifically, a low cuproptosis score foreshadowed good prognosis. DLAT was highly expressed in liver cancer cell lines and HCC tissues and positively correlated with clinical stage and grade. We also found that potent copper ionophore elesclomol could induce cuproptosis in a copper-dependent manner. Selective Cu++ chelator ammonium tetrathiomolybdate and downregulating DLAT expression by siRNA could effectively inhibit cuproptosis.

Conclusion

Cuproptosis and DLAT as a promising biomarker could help to determine the prognosis of HCC and may offer novel insights for effective treatment.

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Authors and Affiliations

  1. Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Fan Gao, Yuan Yuan, Pei-yuan Li & Xing-xing He

  2. Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China

    Yang Ding, Ying Chang & Xing-xing He

  3. Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China

    Ying Chang & Xing-xing He

Authors
  1. Fan Gao
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  2. Yuan Yuan
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  3. Yang Ding
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  4. Pei-yuan Li
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  5. Ying Chang
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  6. Xing-xing He
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Corresponding authors

Correspondence to Ying Chang or Xing-xing He.

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Conflict of Interest Statement

The authors have no conflict of interest.

This research was financially supported by grants from the National Natural Science Foundation of China (No. 82073095, No. 82172938 and No. 81670554) and Science and Technology Innovation Cultivation Fund of Zhongnan Hospital of Wuhan University (No. CXPY2020042).

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Gao, F., Yuan, Y., Ding, Y. et al. DLAT as a Cuproptosis Promoter and a Molecular Target of Elesclomol in Hepatocellular Carcinoma. CURR MED SCI 43, 526–538 (2023). https://doi.org/10.1007/s11596-023-2755-0

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  • DOI: https://doi.org/10.1007/s11596-023-2755-0

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