Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
School of Chemistry, Faculty of Science, The University of Sydney, Sydney, NSW 2006, Australia.
Int J Mol Sci. 2021 Apr 13;22(8):4011. doi: 10.3390/ijms22084011.
Glioblastoma display vast cellular heterogeneity, with glioblastoma stem cells (GSCs) at the apex. The critical role of GSCs in tumour growth and resistance to therapy highlights the need to delineate mechanisms that control stemness and differentiation potential of GSC. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) regulates neural progenitor cell differentiation, but its role in cancer stem cell differentiation is largely unknown. Herein, we demonstrate that DYRK1A kinase is crucial for the differentiation commitment of glioblastoma stem cells. DYRK1A inhibition insulates the self-renewing population of GSCs from potent differentiation-inducing signals. Mechanistically, we show that DYRK1A promotes differentiation and limits stemness acquisition via deactivation of CDK5, an unconventional kinase recently described as an oncogene. DYRK1A-dependent inactivation of CDK5 results in decreased expression of the stemness gene SOX2 and promotes the commitment of GSC to differentiate. Our investigations of the novel DYRK1A-CDK5-SOX2 pathway provide further insights into the mechanisms underlying glioblastoma stem cell maintenance.
胶质母细胞瘤表现出广泛的细胞异质性，以胶质母细胞瘤干细胞 (GSCs) 为顶点。GSCs 在肿瘤生长和对治疗的抵抗中的关键作用突出表明需要阐明控制 GSC 的干性和分化潜能的机制。双特异性酪氨酸磷酸化调节激酶 1A (DYRK1A) 调节神经祖细胞分化，但它在癌症干细胞分化中的作用在很大程度上尚不清楚。本文中，我们证明 DYRK1A 激酶对于胶质母细胞瘤干细胞的分化决定至关重要。DYRK1A 抑制可将 GSCs 的自我更新群体与有效的诱导分化信号隔离开来。在机制上，我们表明 DYRK1A 通过去激活 CDK5 来促进分化并限制干性获得，CDK5 是一种最近被描述为癌基因的非典型激酶。依赖于 DYRK1A 的 CDK5 失活导致干性基因 SOX2 的表达降低，并促进 GSC 向分化方向分化。我们对新型 DYRK1A-CDK5-SOX2 途径的研究为胶质母细胞瘤干细胞维持的机制提供了进一步的见解。
