Caillot M, Bourgeais J, Dakik H, Costé É, Mazure N M, Lelièvre É, Coqueret O, Hérault O, Mazurier F, Sola B
Normandie Univ, INSERM, UNICAEN, Caen, France.
Service d'Hématologie Biologique, CHRU de Tours, Tours, France.
Oncogenesis. 2020 Jul 24;9(7):68. doi: 10.1038/s41389-020-00253-3.
Cancer cells are characterized by the Warburg effect, a shift from mitochondrial respiration to oxidative glycolysis. We report here the crucial role of cyclin D1 in promoting this effect in a cyclin-dependent kinase (CDK)4/6-independent manner in multiple myeloma (MM) cells. We show that the cyclin D1 oncoprotein targets hexokinase 2 (HK2), a major glycolysis regulator, through two original molecular mechanisms in the cytoplasmic and nuclear compartments. In the cytoplasm, cyclin D1 binds HK2 at the outer mitochondrial membrane, and in the nucleus, it binds hypoxia-inducible factor-1α (HIF1α), which regulates HK2 gene transcription. We also show that high levels of HK2 expression are correlated with shorter event-free survival (EFS) and overall survival (OS) in MM patients. HK2 may therefore be considered as a possible target for antimyeloma therapy.
癌细胞的特征是瓦伯格效应，即从线粒体呼吸转变为有氧糖酵解。我们在此报告细胞周期蛋白D1在多发性骨髓瘤（MM）细胞中以细胞周期蛋白依赖性激酶（CDK）4/6非依赖性方式促进这种效应的关键作用。我们表明，细胞周期蛋白D1癌蛋白通过细胞质和细胞核区室中的两种原始分子机制靶向主要的糖酵解调节因子己糖激酶2（HK2）。在细胞质中，细胞周期蛋白D1在线粒体外膜与HK2结合，而在细胞核中，它与调节HK2基因转录的缺氧诱导因子-1α（HIF1α）结合。我们还表明，HK2的高表达水平与MM患者较短的无事件生存期（EFS）和总生存期（OS）相关。因此，HK2可能被视为抗骨髓瘤治疗的一个可能靶点。
