KIF15 is essential for USP10-mediated PGK1 deubiquitination during the glycolysis of pancreatic cancer.
KIF15 is essential for USP10-mediated PGK1 deubiquitination during the glycolysis of pancreatic cancer.
复制标题
DOI：
10.1038/s41419-023-05679-2
复制
发表时间：
2023-02-17
影响因子：
9
通讯作者：
Jiang, Jianxin
中科院分区：
文献类型：
--
作者：
Quan, Gang;Xu, Jian;Wang, Jie;Liu, Xinyuan;Xu, Jichuan;Jiang, Jianxin
糖酵解是胰腺癌(PC)最主要的代谢重编程，其在PC细胞中的潜在机制尚不清楚。在本研究中，我们首次发现KIF15促进PC细胞的糖酵解能力和PC肿瘤的生长。KIF15的表达与PC患者的预后呈负相关。ECAR和OCR测量表明，KIF15基因敲除显著削弱了PC细胞的糖酵解能力。Western blotting显示KIF15基因敲除后糖酵解分子标志物的表达迅速下降。进一步的实验表明，KIF15促进了PGK1的稳定性及其对PC细胞糖酵解的影响。有趣的是，KIF15的过度表达削弱了PGK1的泛素化水平。为了研究KIF15调控PGK1功能的潜在机制，我们进行了质谱学研究。MS和Co-IP分析表明，KIF15促进并增强了PGK1与USP10的结合。泛素化实验证实KIF15募集并促进了USP10对PGK1的作用，从而使PGK1去泛素化。通过构建KIF15截短子，我们发现KIF15通过其coil2结构域与PGK1和USP10结合。总之，我们的研究首次证明KIF15通过募集USP10和PGK1来增强PC的糖酵解能力，KIF15/USP10/PGK1轴可能是一种有效的PC治疗剂。
Glycolysis is the most predominant metabolic reprogramming of pancreatic cancer (PC), the underlying mechanism of which in PC cells remains unclear. In this study, we found for the first time that KIF15 promotes the glycolytic capacity of PC cells and PC tumor growth. Moreover, the expression of KIF15 was negatively correlated with the prognosis of PC patients. The ECAR and OCR measurements indicated that KIF15 knockdown significantly impaired the glycolytic capacity of PC cells. Western blotting demonstrated that the expression of glycolysis molecular markers decreased rapidly after the knockdown of KIF15. Further experiments revealed that KIF15 promoted the stability of PGK1 and its effect on PC cell glycolysis. Interestingly, the overexpression of KIF15 impaired the ubiquitination level of PGK1. To investigate the underlying mechanism by which KIF15 regulates the function of PGK1, we performed mass spectrometry (MS). The MS and Co-IP assay indicated that KIF15 recruited and enhanced the binding between PGK1 and USP10. The ubiquitination assay verified that KIF15 recruited and promoted the effect of USP10 on PGK1, thereby deubiquitinating PGK1. Through the construction of KIF15 truncators, we found that KIF15 is bound to PGK1 and USP10 through its coil2 domain. Together, our study demonstrated for the first time that KIF15 enhances the glycolytic capacity of PC through the recruitment of USP10 and PGK1, and that the KIF15/USP10/PGK1 axis may serve as an effective therapeutic agent for PC.
登录
查看更多内容
DOI：
10.1038/s41575-021-00457-x
发表时间：
2021-07
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
通讯作者：
--
饮食中高的分支链氨基酸通过USP1介导的BCAT2稳定促进PDAC的发展。
影响因子：
20.6
作者：
通讯作者：
--
影响因子：
11.5
作者：
Karasinska, Joanna M.;Topham, James T.;Schaeffer, David F.
通讯作者：
Schaeffer, David F.
影响因子：
6.4
作者：
Zieker, Derek;Koenigsrainer, Ingmar;Tritschler, Isabel;Loeffler, Markus;Beckert, Stefan;Traub, Frank;Nieselt, Kay;Buehler, Sarah;Weller, Michael;Gaedcke, Jochen;Taichman, Russell S.;Northoff, Hinnak;Bruecher, Bjoern L. D. M.;Koenigsrainer, Alfred
通讯作者：
Koenigsrainer, Alfred
影响因子：
16.2
作者：
Shao, Fei;Yang, Xueying;He, Jie
通讯作者：
He, Jie