巴基斯坦卢比
癌症研究
相扑蛋白
生物
厌氧糖酵解
转移
丙酮酸激酶
糖酵解
细胞生物学
化学
生物化学
癌症
泛素
新陈代谢
遗传学
基因
作者
Qiang Zhou,Yuehui Yin,Ming Yu,Dongmei Gao,Jialei Sun,Zhixu Yang,Juyang Weng,Wanyong Chen,Manar Atyah,Ying‐Hao Shen,Qing‐Hai Ye,Chia-Wei Li,Mien‐Chie Hung,Qiongzhu Dong,Chixing Zhou,Ning Ren
出处
期刊:Redox biology
[Elsevier]
日期:2022-10-01
卷期号:56: 102458-102458
被引量:20
标识
DOI:10.1016/j.redox.2022.102458
摘要
Guanosine triphosphate binding protein 4 (GTPBP4) is a key regulator of cell cycle progression and MAPK activation. However, how its biological properties intersect with cellular metabolism in hepatocellular carcinoma (HCC) development remains poorly unexplained. Here, high GTPBP4 expression is found to be significantly associated with worse clinical outcomes in patients with HCC. Moreover, GTPBP4 upregulation is paralleled by DNA promoter hypomethylation and regulated by DNMT3A, a DNA methyltransferase. Additionally, both gain- and loss-of-function studies demonstrate that GTPBP4 promotes HCC growth and metastasis in vitro and in vivo. Mechanically, GTPBP4 can induce dimeric pyruvate kinase M2 (PKM2) formation through protein sumoylation modification to promote aerobic glycolysis in HCC. Notably, active GTPBP4 facilitates SUMO1 protein activation by UBA2, and acts as a linker bridging activated SUMO1 protein and PKM2 protein to induce PKM2 sumoylation. Furthermore, SUMO-modified PKM2 relocates from the cytoplasm to the nucleus may also could contribute to HCC progression through activating epithelial-mesenchymal transition (EMT) and STAT3 signaling pathway. Shikonin, a PKM2-specific inhibitor, can attenuate PKM2 dependent HCC glycolytic reprogramming, growth and metastasis promoted by GTPBP4, which offers a promising therapeutic candidate for HCC patients. Our findings indicate that GTPBP4-PKM2 regulatory axis plays a vital role in promoting HCC proliferation as well as metastasis by aerobic glycolysis and offer a promising therapeutic target for HCC patients.
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