Xu Liuyu, Li Hongyun, Wu Longchao, Huang Shiming
Department of Urology, QianFoShan Hospital Affiliated to Shandong University, Jinan 250014, P. R. China.
Department of Urology, Penglai People's Hospital of Shandong, Penglai 265600, P. R. China.
Oncotarget. 2017 Jul 26;8(39):65946-65956. doi: 10.18632/oncotarget.19583. eCollection 2017 Sep 12.
Aerobic glycolysis, also known as Warburg effect, is a key hallmark of cancers. The Y-box-binding protein 1 (YBX1) is a well-known oncoprotein implicated in multiple malignant phenotypes of cancers. Meanwhile, little is known about the oncogenic functions and mechanisms of YBX1 in bladder cancer. Based on gene set enrichment analysis (GSEA) of TCGA RNAseq data, we find that YBX1 was profoundly involved in the glycolysis part of glucose metabolism. Loss- and gain-of-function studies show that YBX1 can enhance glycolysis as revealed by expression of glycolytic enzymes, glucose uptake, lactate secretion and extracellular acidification rate (ECAR). Inhibition of glycolysis completely compromises the tumor-promoting effect of YBX1 on tumor growth. Mechanistically, YBX1 regulates the expression of c-Myc and HIF1α, which further upregulate glycolytic enzymes to facilitate glycolysis. Moreover, study further confirms that genetic silencing of YBX1 markedly attenuates tumor growth and this tumor-suppressive effect is largely dependent on reduced glycolysis. Taken together, these results, as a proof of principle, provide a novel insight into the oncogenic role of YBX1 in glycolysis and suggest the potential therapeutic strategy by targeting YBX1 in bladder cancer.
有氧糖酵解，也称为瓦伯格效应，是癌症的一个关键特征。Y盒结合蛋白1（YBX1）是一种著名的癌蛋白，与癌症的多种恶性表型有关。与此同时，关于YBX1在膀胱癌中的致癌功能和机制知之甚少。基于对TCGA RNAseq数据的基因集富集分析（GSEA），我们发现YBX1深度参与了葡萄糖代谢的糖酵解部分。功能缺失和功能获得研究表明，YBX1可以增强糖酵解，这通过糖酵解酶的表达、葡萄糖摄取、乳酸分泌和细胞外酸化率（ECAR）得以体现。抑制糖酵解完全消除了YBX1对肿瘤生长的促进作用。从机制上讲，YBX1调节c-Myc和HIF1α的表达，进而上调糖酵解酶以促进糖酵解。此外，研究进一步证实，YBX1的基因沉默显著减弱肿瘤生长，这种肿瘤抑制作用很大程度上依赖于糖酵解的减少。综上所述，这些结果作为一个原理证明，为YBX1在糖酵解中的致癌作用提供了新的见解，并提示了针对膀胱癌中YBX1的潜在治疗策略。
