Chen Huan, Shi Jing, Wang Qiuping, Liang Kunming, Pei Shaojun, Zhang Yi, Shi Xiang, Lv Jing, Xia Tian, Chen Di, Ma Yegang, Liu Hong-Xu, Piao Hai-Long
State Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
State Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China; Department of Biochemistry & Molecular Biology, School of Life Sciences, China Medical University, Shenyang, China.
J Biol Chem. 2025 Aug 12;301(9):110585. doi: 10.1016/j.jbc.2025.110585.
The activation of oncogenes is often accompanied by metabolic adaptations. The DNA/RNA-binding protein, Y-box binding protein 1 (YBX1), a well-known oncogene, is hyperactivated in nearly all cancer types. However, the metabolic hallmarks associated with YBX1 and the underlying mechanisms remain poorly understood. Here, we demonstrate that YBX1 sustains the activity of the pyruvate dehydrogenase (PDH) complex by regulating its catalytic alpha subunit, PDHA1. Mechanistically, YBX1 downregulates the expression of PDH kinases 1 and 4, leading to enhanced PDHA1 activity. Consequently, YBX1 deficiency results in significant impairment of pyruvate oxidation. Moreover, we found that YBX1, in conjunction with PDH activation, promotes epithelial cell senescence and suppresses cancer cell proliferation. These findings indicate that PDH activation imposes a constraint on the tumorigenic potential of YBX1.
癌基因的激活通常伴随着代谢适应。DNA/RNA结合蛋白Y盒结合蛋白1（YBX1）是一种著名的癌基因，在几乎所有癌症类型中都被过度激活。然而，与YBX1相关的代谢特征及其潜在机制仍知之甚少。在这里，我们证明YBX1通过调节其催化性α亚基PDHA1来维持丙酮酸脱氢酶（PDH）复合体的活性。从机制上讲，YBX1下调PDH激酶1和4的表达，导致PDHA1活性增强。因此，YBX1缺乏会导致丙酮酸氧化显著受损。此外，我们发现YBX1与PDH激活一起促进上皮细胞衰老并抑制癌细胞增殖。这些发现表明，PDH激活对YBX1的致瘤潜力施加了限制。
