Liu Shengzhi, Cai Jin, Qian Xiaoyu, Zhang Junjiao, Zhang Yi, Meng Xiang, Wang Mingjie, Gao Ping, Zhong Xiuying
https://ror.org/0530pts50 School of Medicine, South China University of Technology, Guangzhou, China.
https://ror.org/045kpgw45 Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
Life Sci Alliance. 2025 Mar 19;8(6). doi: 10.26508/lsa.202402978. Print 2025 Jun.
Targeting protein for Xklp2 (TPX2) is critical for mitosis and spindle assembly because of its control of Aurora kinase A (AURKA). However, the regulation of TPX2 activity and its subsequent effects on mitosis and cancer progression remain unclear. Here, we show that TPX2 is lactylated at K249 in hepatocellular carcinoma (HCC) tumour tissues and that this process is regulated by the lactylase CBP and the delactylase HDAC1. Lactate reduction via either shRNAs targeting lactate dehydrogenase A or the lactate dehydrogenase A inhibitor GSK2837808A decreases the level of TPX2 lactylation. Importantly, TPX2 lactylation is required for the cell cycle regulation and tumour growth. Mechanistically, TPX2 lactylation disrupts protein phosphatase 1 (PP1) binding to AURKA, enhances AURKA T288 phosphorylation, and facilitates the cell cycle progression. Overall, our study reveals a previously unappreciated role of TPX2 lactylation in regulating cell cycle progression and HCC tumorigenesis, exposing an important correlation between metabolic reprogramming and cell cycle regulation in HCC.
靶向Xklp2的蛋白（TPX2）对有丝分裂和纺锤体组装至关重要，因为它能调控极光激酶A（AURKA）。然而，TPX2活性的调节及其对有丝分裂和癌症进展的后续影响仍不清楚。在此，我们表明在肝细胞癌（HCC）肿瘤组织中，TPX2在K249位点发生乳酸化修饰，且该过程受乳酸化酶CBP和去乳酸化酶HDAC1调控。通过靶向乳酸脱氢酶A的短发夹RNA（shRNAs）或乳酸脱氢酶A抑制剂GSK2837808A降低乳酸水平，可降低TPX2的乳酸化水平。重要的是，TPX2乳酸化对于细胞周期调控和肿瘤生长是必需的。从机制上讲，TPX2乳酸化破坏蛋白磷酸酶1（PP1）与AURKA的结合，增强AURKA T288位点的磷酸化，并促进细胞周期进程。总体而言，我们的研究揭示了TPX2乳酸化在调节细胞周期进程和HCC肿瘤发生中以前未被认识的作用，揭示了HCC中代谢重编程与细胞周期调控之间的重要关联。
