Deficiency of TOP1MT enhances glycolysis through the stimulation of PDK4 expression in gastric cancer

IF 6 3区医学 Q1 CELL BIOLOGY

Cancer & Metabolism Pub Date : 2024-01-10 DOI:10.1186/s40170-024-00330-w

Hongqiang Wang, Xutao Sun, Chen Yang, Ziqi Li, Danwen Jin, Wenwen Zhu, Ze Yu

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Abstract

Abnormal glucose metabolism is one of the determinants of maintaining malignant characteristics of cancer. Targeting cancer metabolism is regarded as a new strategy for cancer treatment. Our previous studies have found that TOP1MT is a crucial gene that inhibits glycolysis and cell metastasis of gastric cancer (GC) cells, but the mechanism of its regulation of glycolysis remains unclear. Transcriptome sequencing data, clinic-pathologic features of GC from a variety of public databases, and WGCNA were used to identify novel targets of TOP1MT. Immunohistochemical results of 250 patients with GC were used to analyze the relative expression relationship between TOP1MT and PDK4. The function of TOP1MT was investigated by migration assays and sea-horse analysis in vitro. We discovered a mitochondrial topoisomerase I, TOP1MT, which correlated with a higher risk of metastasis. Functional experiments revealed that TOP1MT deficiency promotes cell migration and glycolysis through increasing PDK4 expression. Additionally, the stimulating effect of TOP1MT on glycolysis may be effectively reversed by PDK4 inhibitor M77976. In brief, our work demonstrated the critical function of TOP1MT in the regulation of glycolysis by PDK4 in gastric cancer. Inhibiting glycolysis and limiting tumor metastasis in GC may be accomplished by suppressing PDK4.

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缺乏 TOP1MT 会通过刺激 PDK4 的表达增强胃癌中的糖酵解作用

葡萄糖代谢异常是维持癌症恶性特征的决定因素之一。靶向癌症代谢被认为是治疗癌症的新策略。我们之前的研究发现，TOP1MT是抑制胃癌（GC）细胞糖酵解和细胞转移的关键基因，但其调控糖酵解的机制仍不清楚。研究人员利用转录组测序数据、来自各种公共数据库的胃癌临床病理特征以及 WGCNA 来确定 TOP1MT 的新靶点。利用 250 例 GC 患者的免疫组化结果分析了 TOP1MT 和 PDK4 的相对表达关系。通过迁移试验和体外海马分析研究了TOP1MT的功能。我们发现线粒体拓扑异构酶 I TOP1MT 与转移风险较高有关。功能实验显示，TOP1MT 的缺乏可通过增加 PDK4 的表达促进细胞迁移和糖酵解。此外，PDK4抑制剂M77976可有效逆转TOP1MT对糖酵解的刺激作用。简而言之，我们的工作证明了 TOP1MT 在胃癌中通过 PDK4 调节糖酵解的关键功能。抑制 PDK4 可抑制糖酵解并限制胃癌的肿瘤转移。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer & Metabolism Multiple-

自引率

1.70%

发文量

审稿时长

14 weeks

期刊介绍： Cancer & Metabolism welcomes studies on all aspects of the relationship between cancer and metabolism, including: -Molecular biology and genetics of cancer metabolism -Whole-body metabolism, including diabetes and obesity, in relation to cancer -Metabolomics in relation to cancer; -Metabolism-based imaging -Preclinical and clinical studies of metabolism-related cancer therapies.