Li Xuetao, Chen Guangliang, Liu Bin, Tao Zhennan, Wu Yue, Zhang Kai, Feng Zibin, Huang Yulun, Wang Hao
Department of Neurosurgery, Dushu Lake Hospital Affiliated of Soochow University, Suzhou, Jiangsu, China.
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Cell Death Discov. 2023 Feb 17;9(1):68. doi: 10.1038/s41420-023-01302-7.
Glioma stem cells (GSCs) are the important cause of tumorigenesis, recurrence, and chemo(radio)resistance in glioma. Targeting GSCs helps improve the outcomes of glioma treatment. Polo-like kinase 1 (PLK1) is a member of the serine/threonine protein kinase family, which is highly conserved. In recent years, it has been suggested that increased levels of PLK1 and its activity are associated with tumor progression and poor prognosis. We aimed to identify whether PLK1 plays a critical role in stemness maintenance and apoptosis regulation in GSCs. Here we identify that PLK1 inhibition can induce apoptosis and DNA damage of GSCs, we have also delineat the possible underlying molecular mechanisms: PLK1 interacts with YBX1 and directly phosphorylates serine 174 and serine 176 of YBX1. Inhibition of PLK1 reduces the phosphorylation level of YBX1, and decreased phosphorylation of YBX1 prevents its nuclear translocation, thereby inducing apoptosis and DNA damage of GSCs. We confirmed that YBX1 knockdown resulted in the apoptosis and DNA damage of GSCs. These findings uncover that PLK1 inhibition induces cell apoptosis and DNA damage in GSCs through YBX1 phosphorylation, providing new insights into the mechanism by which PLK1 inhibition contributes to the apoptosis of and DNA damage in gliomas.
胶质瘤干细胞（GSCs）是胶质瘤发生、复发及化疗（放疗）耐药的重要原因。靶向GSCs有助于改善胶质瘤的治疗效果。Polo样激酶1（PLK1）是丝氨酸/苏氨酸蛋白激酶家族的成员，具有高度保守性。近年来，有研究表明PLK1水平及其活性的升高与肿瘤进展和不良预后相关。我们旨在确定PLK1在GSCs干性维持和凋亡调控中是否起关键作用。在此我们发现，抑制PLK1可诱导GSCs凋亡和DNA损伤，我们还阐述了可能的潜在分子机制：PLK1与YBX1相互作用并直接磷酸化YBX1的丝氨酸174和丝氨酸176。抑制PLK1可降低YBX1的磷酸化水平，而YBX1磷酸化水平的降低会阻止其核转位，从而诱导GSCs凋亡和DNA损伤。我们证实，敲低YBX1可导致GSCs凋亡和DNA损伤。这些发现揭示，抑制PLK1通过YBX1磷酸化诱导GSCs细胞凋亡和DNA损伤，为PLK1抑制导致胶质瘤细胞凋亡和DNA损伤的机制提供了新见解。
