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.

癌细胞的特点是 Warburg 效应，即从线粒体呼吸到氧化糖酵解的转变。我们在此报告细胞周期蛋白 D1 在多发性骨髓瘤 (MM) 细胞中以不依赖于细胞周期蛋白的激酶 (CDK) 4/6 的方式促进这种作用的关键作用。我们显示细胞周期蛋白 D1 癌蛋白通过细胞质和核区室中的两种原始分子机制靶向己糖激酶 2 (HK2)，一种主要的糖酵解调节剂。在细胞质中，cyclin D1 在线粒体外膜与 HK2 结合，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，高水平的HK2表达与 MM 患者中较短的无事件生存期 (EFS) 和总生存期 (OS) 相关。因此，HK2 可被视为抗骨髓瘤治疗的可能靶点。