Oncogene-derived metabolic reprogramming is important for anabolic growth of cancer cells, which is now considered to be not simply rely on glycolysis. Pentose phosphate pathway and tricarboxylic acid cycle also play pivotal roles in helping cancer cells to meet their anabolic and energy demands. The present work focused on gankyrin, a relatively specific oncogene in hepatocellular carcinoma (HCC), and its impact on glycolysis and mitochondrial homeostasis. Metabolomics, RNA-seq analysis, and subsequent conjoint analysis illustrated that gankyrin regulated the pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, and mitochondrial function and homeostasis, which play pivotal roles in tumor development. Mechanistically, gankyrin was found to modulate HCC metabolic reprogramming via TIGAR. Gankyrin positively regulated the transcription of TIGAR through Nrf2, which bound to the antioxidant response elements (AREs) in the promoter of TIGAR. Interestingly, TIGAR feedback regulated the transcription of Nrf2 and subsequently gankyrin by promoting nuclear importation of PGC1α. The loop between gankyrin, Nrf2, and TIGAR accelerated glucose metabolism toward the PPP and TCA cycle, which provided vital building blocks, such as NADPH, ATP, and ribose of tumor and further facilitated the progression of HCC.

中文翻译：

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Gankyrin 和 TIGAR 协同加速肝细胞癌中 PPP 和 TCA 循环的葡萄糖代谢

癌基因衍生的代谢重编程对于癌细胞的合成代谢生长很重要，现在认为这不仅仅是依靠糖酵解。戊糖磷酸途径和三羧酸循环在帮助癌细胞满足其合成代谢和能量需求方面也起着关键作用。目前的工作重点是 gankyrin，一种在肝细胞癌 (HCC) 中相对特异的致癌基因，及其对糖酵解和线粒体稳态的影响。代谢组学、RNA-seq 分析和随后的联合分析表明，gankyrin 调节磷酸戊糖途径 (PPP)、三羧酸 (TCA) 循环以及线粒体功能和稳态，这些在肿瘤发展中起着关键作用。从机制上讲，gankyrin 被发现可通过 TIGAR 调节 HCC 代谢重编程。Gankyrin 通过 Nrf2 正调控 TIGAR 的转录，Nrf2 与 TIGAR 启动子中的抗氧化反应元件 (AREs) 结合。有趣的是，TIGAR 反馈通过促进 PGC1α 的核输入来调节 Nrf2 和随后的 gankyrin 的转录。gankyrin、Nrf2 和 TIGAR 之间的循环加速了葡萄糖代谢向 PPP 和 TCA 循环，这提供了重要的组成部分，例如肿瘤的 NADPH、ATP 和核糖，并进一步促进了 HCC 的进展。