USP1,即泛素特异性蛋白酶1,是一种重要的去泛素化酶,参与调控多种细胞过程,包括DNA损伤修复、细胞周期调控、代谢和信号传导。USP1通过去除蛋白质上的泛素分子,影响这些蛋白质的稳定性、功能和定位,从而在维持细胞稳态和肿瘤发生发展中发挥关键作用。
USP1在肿瘤发生中具有重要作用。研究发现,在BRCA1基因缺陷的肿瘤细胞中,USP1表达上调。USP1通过与DNA结合并激活,保护复制叉的稳定性,从而促进BRCA1缺陷细胞的存活[1]。此外,USP1还可以通过去泛素化CCAAT/enhancer-binding protein beta (C/EBPβ)来增强其稳定性,进而加速脂肪生成和脂质积累[2]。在T细胞急性淋巴母细胞白血病(T-ALL)中,USP1表达上调与不良预后相关。USP1通过去泛素化PLK1来促进乳酸脱氢酶A(LDHA)的表达,从而促进T-ALL细胞的有氧糖酵解和增殖[3]。在复发性/难治性B细胞淋巴瘤中,USP1通过去泛素化MAX蛋白来维持其稳定性,从而促进MYC基因的转录,导致化疗耐药[4]。在骨肉瘤细胞中,USP1表达上调,通过去泛素化多种蛋白质,包括SIK2、MMP-2、GSK-3β、Bcl-2、Stat3、cyclin E1、Notch1、Wnt-1和cyclin A1,从而促进细胞的增殖和侵袭[5]。在Ewing肉瘤细胞中,USP1通过去泛素化Survivin蛋白来维持其稳定性,从而减轻复制压力并促进细胞存活[6]。在人巨细胞病毒(HCMV)感染中,USP1通过与病毒蛋白UL138相互作用,激活STAT1信号通路,从而影响病毒潜伏的建立[7]。USP1还可以通过自切割和降解来调节其活性,从而影响DNA交联修复[8]。USP1还可以与WD重复蛋白48(WDR48)形成复合物,从而抑制CSC的分化并促进其增殖[9]。USP1还可以通过去泛素化转录激活因子TAZ来抑制骨肉瘤的生长和转移[10]。
USP1作为去泛素化酶,在维持细胞稳态和肿瘤发生发展中发挥重要作用。USP1通过去泛素化多种蛋白质,影响其稳定性、功能和定位,从而影响DNA损伤修复、细胞周期调控、代谢和信号传导。USP1在多种肿瘤中表达上调,与不良预后相关,并且可以促进肿瘤细胞的有氧糖酵解、增殖、侵袭和化疗耐药。因此,USP1可能成为肿瘤治疗的新靶点。
参考文献:
1. Lim, Kah Suan, Li, Heng, Roberts, Emma A, Zheng, Ning, D'Andrea, Alan D. . USP1 Is Required for Replication Fork Protection in BRCA1-Deficient Tumors. In Molecular cell, 72, 925-941.e4. doi:10.1016/j.molcel.2018.10.045. https://pubmed.ncbi.nlm.nih.gov/30576655/
2. Kim, Myung Sup, Baek, Jung-Hwan, Lee, JinAh, Lee, Kyeong, Chun, Kyung-Hee. 2023. Deubiquitinase USP1 enhances CCAAT/enhancer-binding protein beta (C/EBPβ) stability and accelerates adipogenesis and lipid accumulation. In Cell death & disease, 14, 776. doi:10.1038/s41419-023-06317-7. https://pubmed.ncbi.nlm.nih.gov/38012162/
3. Liu, Shuguang, Xiang, Yuening, Wang, Boshi, Zhang, Hui, Qian, Maoxiang. . USP1 promotes the aerobic glycolysis and progression of T-cell acute lymphoblastic leukemia via PLK1/LDHA axis. In Blood advances, 7, 3099-3112. doi:10.1182/bloodadvances.2022008284. https://pubmed.ncbi.nlm.nih.gov/36912760/
4. Li, Xi-Ya, Wu, Ji-Chuan, Liu, Ping, Zhang, Qun-Ling, Wang, Lan. 2022. Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma. In Leukemia, 37, 164-177. doi:10.1038/s41375-022-01747-2. https://pubmed.ncbi.nlm.nih.gov/36352191/
5. Liu, Jinbo, Zhu, Hongjun, Zhong, Ning, Wang, Hongwei, Wang, Jinzhi. 2016. Gene silencing of USP1 by lentivirus effectively inhibits proliferation and invasion of human osteosarcoma cells. In International journal of oncology, 49, 2549-2557. doi:10.3892/ijo.2016.3752. https://pubmed.ncbi.nlm.nih.gov/27840911/
6. Mallard, Halle J, Wan, Shibiao, Nidhi, Prakriti, Band, Hamid, Ghosal, Gargi. . USP1 Expression Driven by EWS::FLI1 Transcription Factor Stabilizes Survivin and Mitigates Replication Stress in Ewing Sarcoma. In Molecular cancer research : MCR, 21, 1186-1204. doi:10.1158/1541-7786.MCR-23-0323. https://pubmed.ncbi.nlm.nih.gov/37478161/
7. Zarrella, Kristen, Longmire, Pierce, Zeltzer, Sebastian, Nelson, Jay A, Goodrum, Felicia. 2023. Human cytomegalovirus UL138 interaction with USP1 activates STAT1 in infection. In PLoS pathogens, 19, e1011185. doi:10.1371/journal.ppat.1011185. https://pubmed.ncbi.nlm.nih.gov/37289831/
8. Kim, Mira, Kim, Jung Min. 2016. The role of USP1 autocleavage in DNA interstrand crosslink repair. In FEBS letters, 590, 340-8. doi:10.1002/1873-3468.12060. https://pubmed.ncbi.nlm.nih.gov/26783108/
9. Goncalves, Jussara Maria, Cordeiro, Mabel Mariela Rodriguez, Rivero, Elena Riet Correa. . The Role of the Complex USP1/WDR48 in Differentiation and Proliferation Processes in Cancer Stem Cells. In Current stem cell research & therapy, 12, 416-422. doi:10.2174/1574888X12666170315104013. https://pubmed.ncbi.nlm.nih.gov/28302046/
10. Yuan, Putao, Feng, Zhenhua, Huang, Hai, Shi, Peihua, Sun, Xuewu. 2022. USP1 inhibition suppresses the progression of osteosarcoma via destabilizing TAZ. In International journal of biological sciences, 18, 3122-3136. doi:10.7150/ijbs.65428. https://pubmed.ncbi.nlm.nih.gov/35637948/