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

作者：Fan Gao, Yuan Yuan, Yang Ding, Pei-yuan Li, Ying Chang & Xing-xing He

编辑推读

该项研究为我们揭示了肝细胞癌（HCC）中铜死亡（cuproptosis）的分子机制及其潜在的治疗应用。铜死亡，作为一种新近发现的细胞死亡途径，与传统的凋亡、坏死等途径截然不同，为癌症治疗提供了全新的视角。

本研究的作者团队来自武汉大学中南医院何星星教授课题组，得到了国家自然科学基金及武汉大学中南医院科学技术创新培育基金的资助。研究团队通过综合应用生物信息学分析、实验验证等手段，构建了一个能够量化HCC中铜死亡特征的模型，并发现了与铜死亡密切相关的关键基因DLAT。

研究显示，HCC可以根据铜死亡相关基因的表达被分为三种不同的分子亚型，其中第二组亚型的免疫细胞浸润最多，预后最佳。更重要的是，研究团队发现铜离子载体Elesclomol能够在铜依赖性方式下诱导HCC细胞发生铜死亡，而通过siRNA降低DLAT表达或使用铜离子螯合剂能有效抑制这一过程。

这项研究不仅丰富了我们对HCC分子机制的认识，更为HCC的临床治疗提供了新的思路。铜死亡特征作为一种有前景的生物标志物，不仅有助于预测HCC的预后，还可能指导未来的个性化治疗策略。我们推荐广大医学科研工作者关注这一领域的最新进展，共同推动肝癌治疗的创新与发展。

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

// 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.